Benzodiazepine compound and pharmaceutical composition

ABSTRACT

The present invention provides a novel benzodiazepine compound that blocks the I Kur  current or the Kv1.5 channel potently and more selectively than other K +  channels. The benzodiazepine compound of the invention is represented by General Formula (1) 
     
       
         
         
             
             
         
       
         
         wherein R 1 , R 2 , R 3 , and R 4  are each independently hydrogen or lower alkyl; R 2  and R 3  may be linked to form lower alkylene; 
         A 1  is lower alkylene optionally substituted with one or more hydroxy; and 
         R 5  is group represented by 
       
    
     
       
         
         
             
             
         
       
         
         wherein R 6  and R 7  are each independently hydrogen or organic group; 
         X A  and X B  are each independently bond, lower alkylene, etc.

TECHNICAL FIELD

The present invention relates to a benzodiazepine compound and apharmaceutical composition.

BACKGROUND ART

Atrial fibrillation (hereinafter referred to as “AF”) is the mostfrequently observed type of arrhythmia in clinical examinations.Although not a lethal arrhythmia, AF causes cardiogenic cerebralembolism, and is therefore recognized as an arrhythmia that greatlyaffects vital prognoses and QOL. It is known that the onset of AFincreases with age, and that repeated AF strokes lead to chronic(serious) AF (The Journal of American Medical Association, 285,2370-2375 (2001) and Circulation, 114, 119-123 (2006)).

To prevent chronic AF, which causes difficulty in restoring sinus rhythmand increases the risk of cardiogenic cerebral embolism, earlydefibrillation and subsequent prevention of recurrence (maintenance ofthe sinus rhythm) are required. Antiarrhythmic drugs (classes I and III)are most commonly used as pharmacotherapy, but these drugs achieveinsufficient therapeutic effects, while causing serious side effectssuch as a proarrhythmic effect (Am. J. Cardiol., 72, B44-B49 (1993)).

The onset of AF is triggered by atrial premature contraction withunderlining causes such as intra-atrial conduction delay, shortening andheterogeneity of the atrial refractory period (Nature Reviews DRUGDISCOVERY 4, 899-910 (2005)). It is known that the prolongation ofrefractory period of atrial muscle can terminate AF (defibrillation) orprevent the occurence of AF. The action potential duration of themammalian cardiac muscle is predominantly determined byvoltage-dependent K⁺ channels. Inhibition of the K⁺ channel prolongsmyocardial action potential duration, which results in prolongation ofthe refractory period (Nature Reviews DRUG DISCOVERY 5, 1034-49 (2006)).The action mechanism of class III antiarrhythmic drugs (e.g.,Dofetilide) is to inhibit rapid delayed rectifier K⁺ current (I_(Kr)),K⁺ current encoded by HERG. However, since I_(Kr) is present in both theatria and ventricles, such drugs might cause ventricular arrhythmias,such as torsades de pointes (Trends Pharmacol. soc., 22, 240-246(2001)).

Ultra-rapid delayed rectifier K⁺ current (I_(Kur)), K⁺ current encodedby Kv1.5, has been identified as K⁺ channel that is specificallyexpressed only in human atria (Cric. Res., 73, 1061-1076 (1993), J.Physiol., 491, 31-50 (1996) and Cric. Res., 80, 572-579 (1997)).Muscarine potassium current (I_(KACh)) encoded by two genes called GIRK1and GIRK4 is known as a K⁺ channel specifically expressed in human atria(Nature 374, 135-141 (1995)). Accordingly, a pharmacologicallyacceptable substance that selectively blocks the I_(Kur) current (theKv1.5 channel) or the I_(KAch) current (GIRK1/4 channel) can actselectively on the atrial muscle and is considered effective to excludethe proarrhythmic effect caused by prolonged action potential durationof the ventricular muscle.

DISCLOSURE OF THE INVENTION

The present inventors conducted extensive research to develop a compoundthat blocks the I_(Kur) current (Kv1.5 channel) and/or the I_(KAch)current (GIRK1/4 channel) potently and more selectively than other K⁺channels. As a result, the inventors found that a novel benzodiazepinecompound represented by General Formula (1) below could be the desiredcompound. The present invention has been accomplished based on the abovefindings.

The present invention provides benzodiazepine compounds, andpharmaceutical compositions comprising the benzodiazepine compounds assummarized in items 1 to 13 below.

-   Item 1. A benzodiazepine compound represented by General Formula (1)

-   or a salt thereof,-   wherein R¹, R², R³, and R⁴ are each independently hydrogen or lower    alkyl;-   R² and R³ may be linked to form lower alkylene;-   A¹ is lower alkylene optionally substituted with one or more    hydroxy; and-   R⁵ is group represented by

-   wherein R⁶ and R⁷ are each independently hydrogen or organic group;-   X_(A) and X_(B) are each independently bond, lower alkylene, lower    alkenylene, —CO—, —SO₂—, —SO₂-lower alkylene, —CO-lower alkylene,    —CO-lower alkenylene, lower alkylene-N(lower alkyl)-CO-lower    alkylene, lower alkylene-N(lower alkyl)-, lower alkylene-N(lower    alkyl)-CO— or lower alkylene-O—.-   Item 2. A benzodiazepine compound represented by General Formula (1)    or a salt thereof according to item 1,-   wherein R⁶ and R⁷ are each independently hydrogen, lower alkyl,    cyclo lower alkyl, aryl or heterocyclic group.-   Item 3. A benzodiazepine compound represented by General Formula (1)    or a salt thereof according to item 2,-   wherein R⁶ and R⁷ are each independently hydrogen, lower alkyl,    cyclo lower alkyl, aryl or saturated or unsaturated monocyclic or    polycyclic heterocyclic group containing at least one hetero atom    selected from among oxygen, sulfur and nitrogen.-   Item 4. A benzodiazepine compound represented by General Formula (1)    or a salt thereof according to item 3,-   wherein R⁶ and R⁷ are each independently hydrogen, lower alkyl,    cyclo lower alkyl, phenyl, naphthyl, furyl, thienyl, pyrazolyl,    oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, triazolyl, pyridyl,    pyrimidinyl, pyridazinyl, pyrazinyl, imidazo[2,1-b]thiazolyl,    thieno[2,3-b]pyrazinyl, 2,3-dihydroimidazo[2,1-b]thiazolyl,    benzothiazolyl, indolyl, imidazo[1,2-a]pyridyl, benzothienyl,    benzimidazolyl, 2,3-dihydrobenzo[b]furyl, benzofuryl, indazolyl,    furo[2,3-c]pyridyl, furo[3,2-c]pyridyl, thieno[2,3-c]pyridyl,    thieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, benzo[1,3]dioxolyl,    benzisoxazolyl, pyrazolo[2,3-a]pyridyl, indolizinyl,    2,3-dihydroindolyl, isoquinolyl, 1,2,3,4-tetrahydro-1H-isoquinolyl,    carbostyril, 3,4-dihydrocarbostyril, quinolyl, chromanyl,    5,6,7,8-tetrahydroisoquinolyl, 3,4-dihydro-1H-isoquinolyl,    naphthyridinyl, 1,4-benzodioxanyl, cinnolinyl, quinoxalinyl, or    2,3-dihydrobenz-1,4-oxazinyl, each of which is optionally    substituted.-   Item 5. A benzodiazepine compound represented by General Formula (1)    or a salt thereof according to item 4,-   wherein R⁶ and R⁷ are each one of the following (1) to (52):-   (1) hydrogen,-   (2) lower alkyl,-   (3) cyclo lower alkyl,-   (4) phenyl optionally substituted with one or more substituents    selected from the group consisting of the following (4-1) to (4-25):-   (4-1) cyano,-   (4-2) hydroxy,-   (4-3) halogen,-   (4-4) lower alkyl optionally substituted with one or more    substituents selected from the group consisting of halogen,    imidazolyl and morpholinyl,-   (4-5) lower alkoxy optionally substituted with one or more    substituents selected from the group consisting of amino and lower    alkyl amino,-   (4-6) pyridyl,-   (4-7) thienyl,-   (4-8) piperazinyl optionally substituted with one or more lower    alkyl,-   (4-9) phenyl,-   (4-10) pyrazolyl optionally substituted with one or more lower    alkyl,-   (4-11) pyrimidinyl optionally substituted with one or more lower    alkyl,-   (4-12) piperidyl optionally substituted with one or more lower    alkyl,-   (4-13) furyl,-   (4-14) carboxy,-   (4-15) lower alkoxycarbonyl,-   (4-16) amino optionally substituted with one or more substituents    selected from the group consisting of lower alkanoyl and lower    alkylsulfonyl,-   (4-17) lower alkylthio,-   (4-18) triazolyl,-   (4-19) imidazolyl,-   (4-20) pyrrolidinyl optionally substituted with one or more oxo,-   (4-21) lower alkylsulfonyl,-   (4-22) lower alkylenedioxy optionally substituted with one or more    halogen,-   (4-23) nitro,-   (4-24) oxazolyl, and-   (4-25) thiazolyl optionally substituted with one or more lower    alkyl,-   (5) naphthyl,-   (6) furyl optionally substituted with one or more substituents    selected from the group consisting of lower alkyl optionally    substituted with halogen, carboxy, sulfo, pyridyloxy, lower    alkoxycarbonyl and phenyl,-   (7) thienyl optionally substituted with one or more substituents    selected from the group consisting of lower alkyl, lower    alkylenedioxy, carboxy, halogen, pyridyl, lower alkoxy, lower    alkoxycarbonyl, oxazolyl and furyl,-   (8) imidazolyl optionally substituted with one or more substituents    selected from the group consisting of phenyl, lower alkyl and    halogen,-   (9) pyrazolyl optionally substituted with one or more substituents    selected from the group consisting of lower alkyl optionally    substituted with halogen, halogen, phenyl optionally substituted    with lower alkoxy, furyl and thienyl,-   (10) oxazolyl optionally substituted with one or more substituents    selected from the group consisting of lower alkyl and phenyl,-   (11) isoxazolyl optionally substituted with one or more substituents    selected from the group consisting of phenyl, lower alkyl, thienyl    and furyl,-   (12) thiazolyl optionally substituted with one or more substituents    selected from the group consisting of lower alkyl optionally    substituted with lower alkoxy, phenyl and lower alkanoylamino,-   (13) pyrrolyl optionally substituted with one or more substituents    selected from the group consisting of lower alkyl and lower    alkoxycarbonyl,-   (14) triazolyl optionally substituted with one or more lower alkyl,-   (15) pyridyl optionally substituted with one or more substituents    selected from the group consisting of lower alkyl optionally    substituted with halogen, oxo, hydroxy, lower alkoxy, halogen,    pyrrolidinyl, morpholinyl and thienyl,-   (16) pyrimidinyl optionally substituted with one or more    substituents selected from the group consisting of lower alkyl and    phenyl,-   (17) pyridazinyl,-   (18) pyrazinyl,-   (19) imidazo[2,1-b]thiazolyl optionally substituted with one or more    halogen,-   (20) thieno[2,3-b]pyrazinyl,-   (21) 2,3-dihydroimidazo[2,1-b]thiazolyl optionally substituted with    one or more phenyl,-   (22) benzothiazolyl optionally substituted with one or more lower    alkyl,-   (23) indolyl optionally substituted with one or more substituents    selected from the group consisting of lower alkyl, lower alkanoyl    and halogen,-   (24) imidazo[1,2-a]pyridyl optionally substituted with one or more    lower alkyl,-   (25) benzothienyl optionally substituted with one or more lower    alkyl,-   (26) benzimidazolyl optionally substituted with one or more lower    alkyl,-   (27) 2,3-dihydrobenzo[b]furyl,-   (28) benzofuryl optionally substituted with one or more halogen,-   (29) indazolyl optionally substituted with one or more lower alkyl,-   (30) furo[2,3-c]pyridyl optionally substituted with one or more    substituents selected from the group consisting of oxo and lower    alkyl,-   (31) furo[3,2-c]pyridyl optionally substituted with one or more    substituents selected from the group consisting of oxo, lower alkyl    optionally substituted with halogen, halogen, furyl, pyridyl and    phenyl optionally substituted with one or more substituents selected    from the group consisting of amino and lower alkoxy,-   (32) thieno[2,3-c]pyridyl optionally substituted with one or more    substituents selected from the group consisting of oxo group and    lower alkyl,-   (33) thieno[3,2-c]pyridyl optionally substituted with one or more    substituents selected from the group consisting of oxo and lower    alkyl,-   (34) thieno[2,3-b]pyridyl,-   (35) benzo[1,3]dioxolyl optionally substituted with one or more    halogen,-   (36) benzisoxazolyl,-   (37) pyrazolo[2,3-a]pyridyl,-   (38) indolizinyl,-   (39) 2,3-dihydroindolyl optionally substituted with one or more    substituents selected from the group consisting of oxo, lower alkyl    and lower alkanoyl,-   (40) isoquinolyl optionally substituted with one or more    substituents selected from the group consisting of lower alkyl,    halogen and oxo,-   (41) 1,2,3,4-tetrahydro-1H-isoquinolyl optionally substituted with    one or more oxo,-   (42) carbostyril optionally substituted with one or more lower    alkoxy,-   (43) 3,4-dihydrocarbostyril optionally substituted with one or more    lower alkoxy,-   (44) quinolyl optionally substituted with one or more substituents    selected from the group consisting of amino optionally substituted    with one or two lower alkyl, lower alkoxy, lower alkyl and oxo,-   (45) chromanyl optionally substituted with one or more lower alkyl,-   (46) 5,6,7,8-tetrahydroisoquinolyl optionally substituted with one    or more oxo,-   (47) 3,4-dihydro-1H-isoquinolyl optionally substituted with one or    more oxo,-   (48) naphthyridinyl,-   (49) 1,4-benzodioxanyl,-   (50) cinnolinyl,-   (51) quinoxalinyl, or-   (52) 2,3-dihydrobenz-1,4-oxazinyl optionally substituted with one or    more substituents selected from the group consisting of lower alkyl    and oxo.-   Item 6. A benzodiazepine compound represented by General Formula (1)    or a salt thereof according to item 5,-   wherein R⁶ and R⁷ are each one of the following (4a), (6a), (7a),    (15a), (30a), (31a), (32a), (33a), (40a) and (44a):-   (4a) phenyl optionally substituted with one or more substituents    selected from the group consisting of the following (4a-1), (4a-4)    and (4a-6):-   (4a-1) cyano,-   (4a-4) lower alkyl optionally substituted with one or more halogen,    and-   (4a-6) pyridyl,-   (6a) furyl,-   (7a) thienyl,-   (15a) pyridyl optionally substituted with one or more lower alkyl,-   (30a) furo[2,3-c]pyridyl optionally substituted with one or more    oxo,-   (31a) furo[3,2-c]pyridyl optionally substituted with one or more    substituents selected from the group consisting of oxo and lower    alkyl,-   (32a) thieno[2,3-c]pyridyl optionally substituted with one or more    oxo,-   (33a) thieno[3,2-c]pyridyl optionally substituted with one or more    oxo,-   (40a) isoquinolyl optionally substituted with one or more oxo, and-   (44a) quinolyl optionally substituted with one or more oxo.-   Item 7. A benzodiazepine compound represented by General Formula (1)    or a salt thereof according to item 6, which is selected from the    group consisting of the following compounds:-   1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-yl    methylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    trihydrochloride,-   3,3,5-trimethyl-1-propyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-yl    methylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    trihydrochloride,-   1,5-diethyl-3,3-dimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-yl    methylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    trihydrochloride,-   1,3,3,5-tetramethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethyl    amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    trihydrochloride,-   1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    dihydrochloride,-   1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    dihydrochloride,-   N-methyl-N-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)benzamide    dihydrochloride,-   1,3,3,5-tetramethyl-7-{3-[(2-methylbenzyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    dihydrochloride,-   1,3,3,5-tetramethyl-7-{3-[(2-pyridin-3-ylethyl)-(quinolin-4-yl    methyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    trihydrochloride,-   1-ethyl-3,3,5-trimethyl-7-{3-[(3-methylpyridin-4-ylmethyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    trihydrochloride,-   1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    dihydrochloride,-   1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    dihydrochloride,-   4-({[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}methyl)benzonitrile,-   1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]thiophen-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-7-(3-{furan-2-ylmethyl-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   7-{3-[benzyl-(2-pyridin-3-ylethyl)amino]propoxy}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   3-{[[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-ylethyl)amino]methyl}benzonitrile,-   1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylbenzyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   4-({[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}methyl)benzonitrile,-   1-ethyl-3,3,5-trimethyl-7-{3-[[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-(4-trifluoromethylbenzyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylbenzyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]thiophen-2-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    dihydrochloride,-   1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]pyridin-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(4-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-3,3,5-trimethyl-7-(3-{(4-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1,5-dihydro    benzo[b][1,4]diazepine-2,4-dione,-   1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-propylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    dihydrochloride,-   N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide    hydrochloride,-   7-(3-{(2,6-dimethylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione    dihydrochloride,-   N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzamide    hydrochloride, and-   N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide.-   Item 8. A pharmaceutical composition comprising a benzodiazepine    compound represented by Formula (1) or a salt thereof according to    claim 1, and a pharmacologically acceptable carrier.-   Item 9. A pharmaceutical composition according to item 8 for    preventing and/or treating arrhythmia.-   Item 10. A benzodiazepine compound represented by Formula (1) or a    salt thereof according to item 1 for use in the pharmaceutical    composition.-   Item 11. Use of a benzodiazepine compound represented by Formula (1)    or a salt thereof according to item 1 as a pharmaceutical    composition.-   Item 12. Use of a benzodiazepine compound represented by Formula (1)    or a salt thereof according to item 1 for the production of a    pharmaceutical composition.-   Item 13. A method of preventing and/or treating arrhythmia,    comprising administering to a patient a benzodiazepine compound    represented by Formula (1) or a salt thereof according to item 1.

The groups represented by R¹, R², R³, R⁴, R⁵, R⁶, R⁷, A¹, X_(A) andX_(B), in the specification are described below.

Examples of “organic group” include lower alkyl, cyclo lower alkyl, arylsuch as phenyl and naphthyl, heterocyclic group such as the (6) to (52)for R⁶ and R⁷.

Examples of “heterocyclic group” include saturated or unsaturatedmonocyclic or polycyclic heterocyclic group containing at least onehetero atom selected from among oxygen, sulfur and nitrogen. Morepreferable heterocyclic group may be the group such as:

-   -   unsaturated 3 to 8-membered, preferably 5 or 6-membered        heteromonocyclic group containing 1 to 4 nitrogen atom(s), for        example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,        and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl        (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,        2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl,        2H-tetrazolyl, etc.), dihydrotriazinyl (e.g.,        4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.),        etc.;    -   saturated 3 to 8-membered, preferably 5 or 6-membered        heteromonocyclic group containing 1 to 4 nitrogen atom(s), for        example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,        pyrazolidinyl, piperazinyl, etc.;    -   unsaturated condensed 7 to 12-membered heterocyclic group        containing 1 to 5 nitrogen atom(s), for example, indolyl,        dihydroindolyl (e.g., 2,3-dihydroindolyl, etc.), isoindolyl,        indolizinyl, benzimidazolyl, uinolyl, isoquinolyl,        dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl, etc.),        tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydro-1H-isoquinolyl,        5,6,7,8-tetrahydroisoquinolyl, etc.), carbostyril,        dihydrocarbostyril (e.g., 3,4-dihydrocarbostyril, etc.),        indazolyl, benzotriazolyl, tetrazolopyridyl,        tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.),        dihydrotriazolopyridazinyl, imidazopyridyl (e.g.,        imidazo[1,2-a]pyridyl, etc.), naphthyridinyl, cinnolinyl,        quinoxalinyl, pyrazolopyridyl (e.g., pyrazolo[2,3-a]pyridyl,        etc.) etc.;    -   unsaturated 3 to 8-membered, preferably 5 or 6-membered        heteromonocyclic group containing 1 to 2 oxygen atom(s), for        example, furyl, etc.;    -   unsaturated condensed 7 to 12-membered heterocyclic group        containing 1 to 3 oxygen atom(s), for example, benzofuryl,        dihydrobenzofuryl (e.g. 2,3-dihydrobenzo[b]furyl, etc.),        chromanyl, benzodioxanyl (e.g., 1,4-benzodioxanyl, etc.),        dihydrobenzoxazinyl (e.g., 2,3-dihydrobenz-1,4-oxazinyl, etc.),        benzodioxolyl (benzo[1,3]dioxolyl, etc.), etc.;    -   unsaturated 3 to 8-membered, preferably 5 or 6-membered        heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to        3 nitrogen atom(s), for example, oxazolyl, isoxazolyl,        oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,        1,2,5-oxadiazolyl, etc.), etc.;    -   saturated 3 to 8-membered, preferably 5 or 6-membered        heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to        3 nitrogen atom(s), for example, morpholinyl, etc.;    -   unsaturated condensed 7 to 12-membered heterocyclic group        containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),        for example, benzoxazolyl, benzoxadiazolyl, benzisoxazolyl,        furopyridyl (e.g., furo[2,3-b]pyridyl, furo[3,2-c]pyridyl,        etc.), etc.;    -   unsaturated 3 to 8-membered, preferably 5 or 6-membered        heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to        3 nitrogen atom(s), for example, thiazolyl, 1,2-thiazolyl,        thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl,        1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl,        etc.), etc.;    -   saturated 3 to 8-membered, preferably 5 or 6-membered        heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to        3 nitrogen atom(s), for example, thiazolidinyl, etc.;    -   unsaturated 3 to 8-membered, preferably 5 or 6-membered        heteromonocyclic group containing a sulfur atom, for example,        thienyl, etc.;    -   unsaturated condensed 7 to 12-membered heterocyclic group        containing 1 to 3 sulfur atom(s), for example, benzothienyl        (e.g. benzolb]thienyl, etc.),    -   unsaturated condensed 7 to 12-membered heterocyclic group        containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s),        for example, benzothiazolyl, benzothiadiazolyl, thienopyridyl        (e.g., thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl,        thieno[3,2-c]pyridyl, etc.), imidazothiazolyl (e.g.,        imidazo[2,1-b]thiazolyl, etc.), dihydroimidazothiazolyl (e.g.,        2,3-dihydroimidazo[2,1-b]thiazolyl, etc.), thienopyrazinyl        (e.g., thieno[2,3-b]pyrazinyl, etc.), etc. and the like; wherein        said heterocyclic group may be substituted by one or more        suitable substituent(s).

Examples of “lower alkyl” include linear or branched alkyl groups having1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl,isohexyl, and 3-methylpentyl.

Examples of “lower alkylene” include linear or branched alkylene groupshaving 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene,2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene,methylmethylene, ethylmethylene, tetramethylene, pentamethylene, andhexamethylene.

Examples of “cyclo lower alkyl” include linear or branched cyclo alkylhaving 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

Examples of “lower alkoxy” include linear or branched alkoxy groupshaving 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy,neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.

Examples of “halogen” include fluorine, chlorine, bromine, and iodine.

Examples of “lower alkylenedioxy” include linear or branched alkylenegroups having 1 to 4 carbon atoms, such as methylenedioxy,ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.

Examples of “lower alkanoyl” include linear or branched alkanoyl groupshaving 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl,isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.

The term “one or more” may be preferably 1 to 6, more preferably 1 to 3.

The benzodiazepine compound of the present invention represented byFormula (1) or its salt can be produced by, for example, the processesshown in the following reaction formulas.

wherein R¹, R², R³, R⁴, R⁵, and A¹ are the same as above, and X₁ ishalogen or hydroxyl.

The reaction of the compound of Formula (2) with the compound of Formula(3) wherein X₁ is halogen can be performed in a usual inert solvent orwithout using any solvents in the presence or absence of a basiccompound.

Examples of inert solvents include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, andethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene,toluene, and xylene; halogenated hydrocarbons such as dichloromethane,dichloroethane, chloroform, and carbon tetrachloride; lower alcoholssuch as methanol, ethanol, and isopropanol; ketones such as acetone andmethyl ethyl ketone; polar solvents such as dimethylformamide (DMF),dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, andacetonitrile; and mixed solvents of such solvents.

The basic compound may be selected from various known compounds.Examples of such compounds include inorganic bases, for example, alkalimetal hydroxides such as sodium hydroxide, potassium hydroxide, cesiumhydroxide, and lithium hydroxide; alkali metal carbonates such as sodiumcarbonate, potassium carbonate, cesium carbonate, lithium carbonate,lithium hydrogencarbonate, sodium hydrogencarbonate, and potassiumhydrogencarbonate; alkali metals such as sodium and potassium; sodiumamide; sodium hydride; and potassium hydride; and organic bases, forexample, alkali metal alcoholates such as sodium methoxide, sodiumethoxide, potassium methoxide, and potassium ethoxide; triethylamine;tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]nonene-5(DBN); 1,8-diazabicyclo[5.4.0]undecene-7 (DBU); and1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds can be usedsingly or in a combination of two or more.

The above reaction may be performed by adding an alkali metal iodidesuch as potassium iodide or sodium iodide to the reaction system, asrequired.

The compound of Formula (3) is usually used in an amount of at least 0.5moles, and preferably 0.5 to 10 moles, per mole of the compound ofFormula (2).

The basic compound is usually used in an amount of 0.5 to 10 moles, andpreferably 0.5 to 6 moles, per mole of the compound of Formula (2).

The reaction is usually performed at a temperature of 0° C. to 250° C.,and preferably 0° C. to 200° C., and is usually completed in about 1 toabout 80 hours.

The reaction of the compound of Formula (2) with the compound of Formula(3) wherein X₁ is hydroxyl is performed in an appropriate solvent in thepresence of a condensing agent.

Examples of solvents usable herein include water; halogenatedhydrocarbons such as chloroform, dichloromethane, dichloroethane, andcarbon tetrachloride; aromatic hydrocarbons such as benzene, toluene,and xylene; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate,ethyl acetate, and isopropyl acetate; alcohols such as methanol,ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, and methyl cellosolve; aprotic polar solvents such asacetonitrile, pyridine, acetone, N,N-dimethyl formamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures of suchsolvents.

Examples of condensing agents include azocarboxylates such asdi-tert-butyl azodicarboxylate, N,N,N′,N′-tetramethyl azodicarboxamide,1,1′-(Azodicarbonyl)dipiperidine, diethyl azodicarboxylate; andphosphorus compounds such as triphenylphosphine andtri-n-butylphosphine.

In this reaction, the compound (3) is usually used in an amount of atleast 1 mole, and preferably 1 to 2 moles, per mole of the compound (2).

The condensing agent is usually used in an amount of at least 1 mole,and preferably 1 to 2 moles, per mole of the compound (2).

The reaction proceeds usually at 0 to 200° C., and preferably at about 0to about 150° C., and is completed in about 1 to about 10 hours.

wherein R¹, R², R³, R⁴ and A¹ are the same as above.

The reaction converting the compound of Formula (1a) to the compound ofFormula (1b) can be carried out by either reacting the compound (1a)with hydrazine in a suitable solvent, or by hydrolysis. Here, hydrazinehydrate may be used as the hydrazine.

Examples of solvents used for reaction of the hydrazine include water;halogenated hydrocarbons such as chloroform dichloromethane anddichloroethane; aromatic hydrocarbons such as benzene, toluene, andxylene; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate andethyl acetate; and aprotic polar solvents such as N,N-dimethylformamide,dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures ofsuch solvents. Other examples of solvents used for the reaction includealcohols such as methanol, ethanol, propanol, butanol,3-methoxy-1-butanol, ethyl cellosolve or methyl cellosolve;acetonitrile, pyridine, acetone, and mixtures of such solvents.

The hydrazine is usually used in an amount of at least about 1 mole, andpreferably about 1 to about 5 moles, per mole of the compound (1a).

The reaction proceeds usually at about 0 to about 120° C., andpreferably at about 0 to about 100° C., and is usually completed inabout 0.5 to about 5 hours.

The hydrolysis of the compound of Formula (1a) is performed in anappropriate solvent or without using any solvents in the presence of anacid or a basic compound.

Examples of solvents usable herein include water; lower alcohols such asmethanol, ethanol, and isopropanol; ketones such as acetone and methylethyl ketone; ethers such as dioxane, tetrahydrofuran and ethyleneglycol dimethyl ether; fatty acids such as acetic acid and formic acid;and mixtures of such solvents.

Examples of acids include mineral acids such as hydrochloric acids,sulfuric acid and hydrobromic acid; aliphatic acids such as formic acid,acetic acid; and sulfonic acids such as p-toluenesulfonic acid.

Examples of basic compounds include metal carbonates such as sodiumcarbonate and potassium carbonate; and metal hydroxides such as sodiumhydroxide and potassium hydroxide.

The reaction proceeds usually at room temperature to about 200° C., andpreferably at room temperature to about 150° C., and is usuallycompleted in about 10 minutes to 25 hours.

wherein R¹, R², R³, R⁴, R⁵, and A¹ are the same as above, and X₂ ishalogen, alkanesulfonyloxy, or arylsulfonyloxy.

The reaction of the compound of Formula (4) with the compound of Formula(5) is performed under the same reaction conditions as those for thereaction of the compound of Formula (3), in which X₁ is halogen, withthe compound of Formula (2) in Reaction Formula 1.

-   wherein R¹, R², R³, R⁴, R⁶, R⁷ and A¹ are the same as above; and-   R⁸ is hydrogen or lower alkyl;-   provided that the alkylene moiety of —CHR⁷R⁸ contains no more than 6    carbon atoms, and —CHR⁸ is the same as X_(B) in which alkylene is    contained.

The reaction of the compound of Formula (1c) and the compound of Formula(6) is carried out, for example, in the presence of a reducing agent ina suitable solvent or without using any solvents.

Examples of solvents usable herein are water; lower alcohols such asmethanol, ethanol, isopropanol, butanol, tert-butanol and ethyleneglycol; acetonitrile; aliphatic acids such as formic acid and aceticacid; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglymeand diglyme; aromatic hydrocarbons such as benzene, toluene and xylene;halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform, and carbon tetrachloride; and mixtures of such solvents,etc.

Examples of reducing agents are aliphatic acids such as formic acid andacetic acid; aliphatic acid alkali metal salts such as sodium formateand sodium acetate; hydride reducing agents such as sodium borohydride,sodium cyanoborohydride, sodium triacetoxyborohydride and aluminiumlithium hydride; mixtures of such hydride reducing agents; mixtures ofaliphatic acids or aliphatic acid alkali metal salts with hydridereducing agents; catalytic hydrogenation reducing agents such aspalladium black, palladium carbon, platinum oxide, platinum black, Raneynickel, etc.

When an aliphatic acid such as formic acid, or an aliphatic acid alkalimetal salt such as sodium formate or sodium acetate is used as areducing agent, a suitable reaction temperature is usually about roomtemperature to about 200° C., and preferably about 50 to about 150° C.The reaction is usually completed in about 10 minutes to about 10 hours.Such aliphatic acids and aliphatic acid alkali metal salts are usuallyused in a large excess relative to the compound of Formula (1c).

When a hydride reducing agent is used, a suitable reaction temperatureis usually about −80 to about 100° C., and preferably about −80 to about70° C. The reaction is usually completed in about 30 minutes to about 60hours. The hydride reducing agent is usually used in an amount of about1 to about 20 moles, and preferably about 1 to about 10 moles, per moleof the compound of Formula (1c). In particular, when aluminium lithiumhydride is used as a hydride reducing agent, it is preferable to usediethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, or likeethers; or benzene, toluene, xylene, or like aromatic hydrocarbons as asolvent. Trimethylamine, triethylamine, N-ethyldiisopropylamine, or likeamines; or molecular sieves 3A (MS-3A), molecular sieves 4A (MS-4A), orlike molecular sieves may be introduced into the reaction system of thereaction.

When a catalytic hydrogenation reducing agent is used, the reaction isusually carried out at about −30 to about 100° C., and preferably about0 to about 60° C., in a hydrogen atmosphere usually about 1 to about 20atm, and preferably about 1 to about 10 atm, or in the presence offormic acid, ammonium formate, cyclohexene, hydrazine hydrate, or likehydrogen donor. The reaction is usually completed in about 1 to about 12hours. The catalytic hydrogenation reducing agent is usually used in anamount of about 0.1 to about 40 wt. %, and preferably about 1 to about20 wt. %, relative to the compound of Formula (1c).

In the reaction of the compound of Formula (1c) with the compound ofFormula (6), the compound of Formula (6) is usually used in an amount atleast 1 mole, and preferably 1 to 5 moles, per mole of the compound ofFormula (1c).

wherein R¹, R², R³, R⁴, R⁶, R⁶, X_(A), X_(B), A¹ and X₁ are the same asabove.

The reaction of the compound of Formula (1c) with the compound ofFormula (7) is performed under the same reaction conditions as those forthe reaction of the compound of Formula (3) with the compound of Formula(2) in Reaction Formula 1.

wherein R¹, R², R³, R⁴, R⁶, R⁷, X_(A), and A¹ are the same as above, andX_(B), is —SO₂— or —CO—.

The reaction converting the compound of Formula (1f) to the compound ofFormula (1c) can be carried out by hydrolysis. The hydrolysis reactionis performed in an appropriate solvent or without using any solvents inthe presence of an acid or a basic compound.

Examples of useful solvents include water; lower alcohols such asmethanol, ethanol, isopropanol and tert-butanol; ketones such as acetoneand methylethyl ketone; ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme and diglyme; aliphatic acids such as aceticacid and formic acid; esters such as methyl acetate and ethyl acetate;halogenated hydrocarbons such as chloroform, dichloromethane,dichloroethane and carbon tetrachloride; dimethyl sulfoxide;N,N-dimethylformamide; and hexamethylphosphoric triamide; and mixturesof such solvents.

Examples of useful acids include mineral acids such as hydrochloricacid, sulfuric acid and hydrobromic acid; and organic acids such asformic acid, acetic acid, thioglycolic acid, trifluoroacetic acid andsulfonic acid (e.g., p-toluenesulfonic acid). Such acids can be usedsingly or in a combination.

Examples of useful basic compounds include carbonates such as sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate and potassiumhydrogencarbonate; and metal hydroxides such as sodium hydroxide,potassium hydroxide, calcium hydroxide and lithium hydroxide. Such basiccompounds can be used singly or in a combination.

An acid or basic compound is usually used in an amount of at least about1 mole, and preferably about 1 to about 10 moles, per mole of thecompound of Formula (1f).

The reaction advantageously proceeds usually at about 0 to about 200°C., and preferably at about 0 to about 150° C., and usually finishes inabout 10 minutes to about 80 hours.

In Reaction Formula 6, when X_(B), in the compound of Formula (1f) is—SO₂—, the compound of Formula (1c) can be easily produced from thecompound of Formula (1f) when thiol acts on the compound under basicconditions. Any basic compound used in the aforementioned hydrolysisreaction can be used. Examples of thiols include aromatic mercaptanssuch as thiophenol; lower alkyl thiols such as thioglycolic acid; etc.The reaction is performed under the same reaction conditions as thosefor the aforementioned hydrolysis reaction, except that thiol is usuallyused in an amount of at least 0.5 moles, and preferably about 1 to about3 moles per mole of the compound of Formula (1f).

wherein R², R³, R⁴, R⁵, A¹, and X₂ are the same as above, and R^(1a) islower alkyl.

The reaction of the compound of Formula (1g) with the compound ofFormula (8) is performed under the same reaction conditions as those forthe reaction of the compound of Formula (3), in which X₁ is halogen,with the compound of Formula (2) in Reaction Formula 1.

When R⁴ in the compound of Formula (1g) is hydrogen in the reaction, acompound in which the first and fifth positions of the benzodiazepineskeleton are simultaneously substituted with R^(1a) may be produced.

wherein R¹, R², R³, R⁵, A¹, and X₂ are the same as above, and R^(4a) islower alkyl.

The reaction of the compound of Formula (1i) with the compound ofFormula (9) is performed under the same reaction conditions as those forthe reaction of the compound of Formula (3), in which X₁ is halogen,with the compound of Formula (2) in Reaction Formula 1.

When R¹ in the compound of Formula (1i) is hydrogen in the reaction, acompound in which the first and fifth positions of the benzodiazepineskeleton are simultaneously substituted with R^(4a) may be produced.

wherein R¹, R⁴, R⁵, A¹, and X₂ are the same as above, and R^(2a) islower alkyl.

The reaction of the compound of Formula (1k) with the compound ofFormula (10) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (3), in which X₁ is halogen,with the compound of Formula (2) in Reaction Formula 1.

When R¹ and/or R⁴ is hydrogen in the reaction of the compound of Formula(1k) and the compound of Formula (10), the hydrogen may be replaced withR^(2a).

The compound of Formula (2), which is used as a starting material in theabove-mentioned reaction formula, can be easily produced by the processshown in the following reaction formulae.

wherein R², R³, R⁴, R^(1a), and X₂ are the same as above. R⁹ is loweralkoxy, and R¹⁰ is lower alkoxycarbonyl.

In the reaction of the compound of Formula (11) and the compound ofFormula (12), the compound of Formula (11) is reacted with carboxylicacid of the compound of Formula (12) through a usual amide bondformation reaction. Conditions for known amide bond formation reactionscan be easily employed in the above amide formation reaction. Forexample, the following reaction methods can be employed: (A) a mixedacid anhydride method, in which Carboxylic Acid (12) is reacted with analkyl halocarboxylate to form a mixed acid anhydride, which is thenreacted with Amine (11); (B) an active ester method, in which CarboxylicAcid (12) is converted to an activated ester such as a phenyl ester,p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazoleester or the like, or an activated amide with benzoxazoline-2-thione,and the activated ester or amide is reacted with Amine (11); (C) acarbodiimide method, in which Carboxylic Acid (12) is subjected to acondensation reaction with Amine (11) in the presence of an activatingagent such as dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), carbonyldiimidazoleor the like; (D) other methods, for example, a method in whichCarboxylic Acid (12) is converted to a carboxylic anhydride using adehydrating agent such as acetic anhydride, and the carboxylic anhydrideis then reacted with Amine (11), a method in which an ester ofCarboxylic Acid (12) with a lower alcohol is reacted with Amine (11) ata high pressure and a high temperature, a method in which an acid halideof Carboxylic Acid (12), i.e., a carboxylic acid halide, is reacted withAmine (11), etc.

The mixed acid anhydride used in the mixed acid anhydride method (A) canbe obtained by the known Schotten-Baumann reaction, and the obtainedmixed acid anhydride is reacted with Amine (11), usually without beingisolated, to thereby produce the compound of Formula (13). TheSchotten-Baumann reaction is performed in the presence of a basiccompound. Usable basic compounds include compounds conventionally usedin the Schotten-Baumann reaction, such as triethylamine, trimethylamine,pyridine, dimethylaniline, N-ethyldiisopropylamine,dimethylaminopyridine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7(DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and other organic bases;sodium carbonate, potassium carbonate, sodium hydrogencarbonate,potassium hydrogencarbonate and other carbonates; sodium hydroxide,potassium hydroxide, calcium hydroxide and other metal hydroxides;potassium hydride, sodium hydride, potassium, sodium, sodium amide,metal alcoholates such as sodium methylate and sodium ethylate, andother inorganic bases; etc. The reaction is usually performed at about−20 to about 150° C., and preferably at about 0 to about 100° C.,usually for about 5 minutes to about 10 hours, and preferably for about5 minutes to about 5 hours. The reaction of the obtained mixed acidanhydride with Amine (11) is usually carried out at about −20 to about150° C., and preferably at about 10 to about 50° C., usually for about 5minutes to about 30 hours, and preferably for about 5 minutes to about25 hours. Generally, the mixed acid anhydride method is performed in asolvent. Solvents used for conventional mixed acid anhydride methods areusable. Examples of usable solvents include chloroform, dichloromethane,dichloroethane, carbon tetrachloride and other halogenated hydrocarbons;benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether,diisopropyl ether, tetrahydrofuran, dimethoxyethane and other ethers;methyl acetate, ethyl acetate, isopropyl acetate and other esters;N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamideand other aprotic polar solvents; mixtures thereof; etc. Examples ofalkyl halocarboxylates usable in the mixed acid anhydride method includemethyl chloroformate, methyl bromoformate, ethyl chloroformate, ethylbromoformate, isobutyl chloroformate, etc. In this method, CarboxylicAcid (12), an alkyl halocarboxylate, and Amine (11) are preferably usedin equimolear amounts, but each of the alkyl halocarboxylate andCarboxylic Acid (12) can also be used in an amount of about 1 to about1.5 moles per mole of Amine (11).

Method (C), in which a condensation reaction is carried out in thepresence of an activating agent, can be performed in a suitable solventin the presence or absence of a basic compound. Solvents and basiccompounds usable in this method include those mentioned hereinafter assolvents and basic compounds usable in the method in which a carboxylicacid halide is reacted with Amine (11) mentioned above as one of theother methods (D). A suitable amount of activating agent is at least 1mole, and preferably 1 to 5 moles per mole of Amine (11). When using WSCas an activating agent, addition of 1-hydroxybenzotriazol to thereaction system enables the reaction to proceed advantageously. Thereaction is usually performed at about −20 to about 180° C., andpreferably at about 0 to about 150° C., and is usually completed inabout 5 minutes to about 90 hours.

When the method in which a carboxylic acid halide is reacted with Amine(11), mentioned above as one of the other methods (D), is employed, thereaction is performed in the presence of a basic compound in a suitablesolvent. Usable basic compounds include a wide variety of known basiccompounds, such as those for use in the Schotten-Baumann reactiondescribed above. Usable solvents include, in addition to those usable inthe mixed acid anhydride method, methanol, ethanol, isopropanol,propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve,methylcellosolve and other alcohols; acetonitrile; pyridine; acetone;water; etc. The ratio of the carboxylic acid halide to Amine (11) is notlimited and can be suitably selected from a wide range. It is usuallysuitable to use, for example, at least about 1 mole, and preferablyabout 1 to about 5 moles of the carboxylic acid halide per mole of Amine(11). The reaction is usually performed at about −20 to about 180° C.,and preferably at about 0 to about 150° C., and usually completed inabout 5 minutes to about 30 hours.

The amide bond formation reaction shown in Reaction Formula 10 can alsobe performed by reacting Carboxylic Acid (12) with Amine (11) in thepresence of a phosphorus compound serving as a condensing agent, such astriphenylphosphine, diphenylphosphinyl chloride,phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate,diethyl cyanophosphate, diphenylphosphoric azide,bis(2-oxo-3-oxazolidinyl)phosphinic chloride or the like.

The reaction is carried out in the presence of a solvent and a basiccompound usable for the method in which a carboxylic acid halide isreacted with Amine (11), usually at about −20 to about 150° C., andpreferably at about 0 to about 100° C., and is usually completed inabout 5 minutes to about 30 hours. It is suitable to use each of thecondensing agent and Carboxylic Acid (12) in amounts of at least about 1mole, and preferably about 1 to about 2 moles per mole of Amine (11).

The reaction converting the compound of Formula (13) to the compound ofFormula (14) can be carried out by, for example, (1) reducing thecompound of Formula (13) in a suitable solvent using a catalytichydrogenation reducing agent, or (2) reducing the compound of Formula(13) in a suitable inert solvent using as a reducing agent a mixture ofan acid with a metal or metal salt, a mixture of a metal or metal saltwith an alkali metal hydroxide, sulfide, or ammonium salt, or the like.

When using Method (1) in which a catalytic hydrogenation reducing agentis used, examples of usable solvents are water; acetic acid; alcoholssuch as methanol, ethanol and isopropanol; hydrocarbons such as n-hexaneand cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl etherand diethylene glycol dimethyl ether; esters such as ethyl acetate andmethyl acetate; aprotic polar solvents such as N,N-dimethylformamide;mixtures of such solvents; etc. Examples of usable catalytichydrogenation reducing agents include palladium, palladium black,palladium carbon, platinum carbon, platinum, platinum black, platinumoxide, copper chromite, Raney nickel, etc. A reducing agent is usuallyused in an amount of about 0.02 times to equal to the weight of thecompound of Formula (13). The reaction temperature is usually about −20to about 150° C., and preferably about 0 to about 100° C. The hydrogenpressure is usually about 1 to 10 atm. The reaction is usually completedin about 0.5 to about 100 hours. An acid such as hydrochloric acid maybe introduced into the reaction system of the reaction.

When using Method (2) above, a mixture of iron, zinc, tin, or tin (II)chloride, with a mineral acid such as hydrochloric acid, or sulfuricacid; or a mixture of iron, iron (II) sulfate, zinc, or tin, with analkali metal hydroxide such as sodium hydroxide, a sulfide such asammonium sulfide, aqueous ammonia solution, or an ammonium salt such asammonium chloride, or the like can be used as a reducing agent. Examplesof inert solvents are water; acetic acid; alcohols such as methanol andethanol; ethers such as dioxane; mixtures of such solvents, etc.Conditions for the reduction reaction can be suitably selected accordingto the reducing agent to be used. For example, when a mixture of tin(II) chloride and hydrochloric acid is used as a reducing agent, it isadvantageous to carry out the reaction at about 0 to about 150° C. forabout 0.5 to about 10 hours. A reducing agent is used in an amount of atleast 1 mole, and preferably about 1 to 5 moles, per mole of thecompound of Formula (13).

The reaction converting the compound of Formula (14) to the compound ofFormula (15) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (11) with the compound ofFormula (12).

The reaction of the compound of Formula (15) with the compound ofFormula (8) is performed under the same reaction conditions as those forthe reaction of the compound of Formula (1g) with the compound ofFormula (8) in Reaction Formula 7.

wherein R¹, R^(2a), R⁴, R⁹, and X₂ are the same as above.

The reaction of the compound of Formula (17) with the compound ofFormula (10) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (3), in which X₁ is halogen,with the compound of Formula (2) in Reaction Formula 1.

When R¹ and/or R⁴ is hydrogen in the reaction of the compound of Formula(17) and the compound of Formula (10), the hydrogen atom may be replacedwith R^(2a).

wherein R¹, R² R³, R⁴, and R⁹ are the same as above.

The reaction converting the compound of Formula (16) to the compound ofFormula (2) can be carried out in a suitable solvent in the presence ofan acid. Examples of solvents include water; lower alcohols such asmethanol, ethanol, and isopropanol; ethers such as dioxane,tetrahydrofuran, and diethyl ether; halogenated hydrocarbons such asdichloromethane, chloroform, and carbon tetrachloride; polar solventssuch as acetonitrile; and mixtures of such solvents. Examples of acidsinclude mineral acids such as hydrochloric acid, sulfuric acid, andhydrobromic acid; aliphatic acids such as formic acid, and acetic acid;sulfonic acids such as p-toluenesulfonic acid; Lewis acids such as boronfluoride, aluminium chloride, and boron tribromide; iodides such assodium iodide, and potassium iodide; mixtures of such iodides and Lewisacids. The reaction is usually performed at about 0 to about 200° C.,and preferably at about 0 to about 150° C., and is usually completed inabout 0.5 to about 25 hours. An acid is usually used in an amount of 1to 10 moles, and preferably about 1 mole to about 2 moles per mole ofthe compound of Formula (16).

The compound of Formula (16) can be prepared using the processes shownin Reaction Formulae 13 and 14 below.

wherein R¹, R², R³, R⁴, and R⁹ are the same as above.

The reaction of the compound of Formula (18) with the compound ofFormula (19) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (11) with the compound ofFormula (12) in Reaction Formula 10.

wherein R¹, R², R³, R^(4a), and R⁹ are the same as above.

The reaction of the compound of Formula (20) with the compound ofFormula (9) is performed under the same reaction conditions as those forthe reaction of the compound of Formula (1i) with the compound ofFormula (9) in Reaction Formula 8.

When R¹ in the compound of Formula (20) is hydrogen in the reaction, acompound in which the first and fifth positions of the benzodiazepineskeleton are simultaneously substituted with R^(4a) may be produced.

The compound of Formula 4, which is used as a starting material in theabove-mentioned reaction formula, can be easily prepared by the processshown in the following reaction formula.

wherein R¹, R², R³, R⁴, A¹, and X₂ are the same as above, and X₃ ishalogen.

The reaction of the compound of Formula (2) with the compound of Formula(21) is performed under the same reaction conditions as those for thereaction of the compound of Formula (3), in which X₁ is halogen, withthe compound of Formula (2) in Reaction Formula 1.

X₂ in the compound of Formula (4) can be replaced with another halogenatom by adding it to an appropriate solvent with an alkali metal halide,and heating under reflux. Examples of alkali metal halides includesodium iodide, sodium bromide, sodium fluoride, sodium chloride,potassium iodide, potassium bromide, potassium fluoride, potassiumchloride, etc. Examples of solvents for halogen exchange include ketonessuch as acetone, 2-butanone; ethers such as dioxane, tetrahydrofuran,diethyl ether, diethylene glycol dimethyl ether, and ethylene glycoldimethyl ether; and esters such as methyl acetate and ethyl acetate.Such solvents can be used singly or in a combination of two or more. Analkali metal halide is usually used in an amount at least 1 mole, andpreferably about 1 mole to about 10 moles, per mole of the compound ofFormula (4). Heat-reflux is continued until the reaction finishes. Forexample, heat-reflux is preferably continued for about 1 to about 15hours. The heat-reflux temperature varies according to the solvent to beused, and is usually about 0 to about 150° C., and preferably about 0 toabout 100° C.

The compound of Formula (5), which is used as a starting material, canbe easily prepared by the process shown in the following reactionformula.

wherein R⁶, R⁷, X_(A), X_(B), X₁, and R⁸ are the same as above.

The reaction of the compound of Formula (5a) with the compound ofFormula (6) is performed under the same reaction conditions as those forthe reaction of the compound of Formula (1c) with the compound ofFormula (6) in Reaction Formula 4.

The reaction of the compound of Formula (5a) with the compound ofFormula (7) is performed under the same reaction conditions as those forthe reaction of the compound of Formula (1c) with the compound ofFormula (7) in Reaction Formula 5.

The compound of Formula (3), which is used as a starting material, canbe easily prepared by the process shown in the following reactionformula.

Starting material (24) used in the following Reaction Formula 18 can beeasily prepared by the process shown in Reaction Formula 17.

wherein A¹ and X_(A) are the same as above, X_(1′) is halogen, andR^(6a) is the same as R⁶ as defined above, excluding the hydrogen atom.

The reaction of the compound of Formula (22) with the compound ofFormula (23) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (2) with the compound ofFormula (3) in Reaction Formula 1.

wherein R⁶, R⁷, X_(A), X_(B), A¹, X₁ and X₂ are the same as above, andR¹¹ is lower alkylsulfonyl. X₄ is halogen, and M is alkali metal such assodium, potassium, etc.

Examples of the lower alkylsulfonyl groups represented by R¹¹ includelinear or branched C₁₋₆ alkylsulfonyl groups, such as methylsulfonyl,ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl,isobutylsulfonyl, tert-butylsulfonyl, sec-butylsulfonyl,n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl,isohexylsulfonyl, and 3-methylpentylsulfonyl.

The reaction of the compound of Formula (24) and the compound of Formula(25) is performed in a suitable solvent or without using any solvents inthe presence of an acid. Examples of solvents include the solvents usedin the reaction of the compound of Formula (2) and the compound ofFormula (3) in Reaction Formula 1. Examples of usable acids includemineral acids such as hydrochloric acid, sulfuric acid, and hydrobromicacid; and organic acids such as formic acid, acetic acid, thioglycolicacid, trifluoroacetic acid, and sulfonic acid (e.g., p-toluenesulfonicacid). Such acids can be used singly or in a combination. Conditionsother than those described above may be the same as those of thereaction between the compound of Formula (2) and the compound of Formula(3) in Reaction Formula 1.

The reaction of the compound of Formula (26) with the compound ofFormula (7) is performed under the same reaction conditions as those forthe reaction of the compound of Formula (2) with the compound of Formula(3) in Reaction Formula 1.

The reaction of the compound of Formula (5c) with the compound ofFormula (28) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (3), in which X₁ is halogen,with the compound of Formula (2) in Reaction Formula 1.

The reaction converting the compound of Formula (27) to the compound ofFormula (3a) can be carried out in an appropriate solvent or withoutusing any solvents in the presence of an acid or a basic compound.

Examples of useful solvents include water; lower alcohols such asmethanol, ethanol, isopropanol, and tert-butanol; ketones such asacetone, and methyl ethyl ketone; ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme and diglyme; aliphatic acids such as aceticacid and formic acid; esters such as methyl acetate and ethyl acetate;halogenated hydrocarbons such as chloroform, dichloromethane,dichloroethane, and carbon tetrachloride; dimethyl sulfoxide;N,N-dimethylformamide; and hexamethylphosphoric triamide; and mixturesof such solvents.

Examples of acids include mineral acids such as hydrochloric acid,sulfuric acid, and hydrobromic acid; and organic acids such as formicacid, acetic acid, trifluoroacetic acid, and sulfonic acid (e.g.,p-toluenesulfonic acid and pyridinium p-toluenesulfonate); Lewis acidssuch as boron tribromide and boron trichloride. Such acids can be usedsingly or in a combination.

Examples of useful basic compounds include carbonates such as sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, and potassiumhydrogencarbonate; and metal hydroxides such as sodium hydroxide,potassium hydroxide, calcium hydroxide, and lithium hydroxide. Suchbasic compounds can be used singly or in a combination.

The reaction advantageously proceeds usually at about 0 to about 200°C., and preferably at about 0 to about 150° C., and is usually completedin about 10 minutes to about 50 hours.

The reaction of the compound of Formula (3a) with the compound ofFormula (29) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (5c) with the compound ofFormula (28).

The reaction converting the compound of Formula (30) to the compound ofFormula (3b) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (3), in which X₁ is halogen,with the compound of Formula (2) in Reaction Formula 1.

The compound of Formula (7), which is used as a starting material, canbe easily prepared by the process shown in the following reactionformula.

wherein R₇, X_(B), X² and A¹ are the same as above.

The reaction of the compound of Formula (32) with the compound ofFormula (28) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (5c) with the compound ofFormula (28) in Reaction Formula 18.

The reaction converting the compound of Formula (33) to the compound ofFormula (7a) can be carried out under the same reaction conditions asthose for the reaction converting the compound of Formula (27) to thecompound of Formula (3a) in Reaction Formula 18.

The compound of Formula (5), which is used as a starting material, canbe easily prepared by the process shown in the following reactionformula.

wherein A¹, R⁷, X_(B), and X₂ are the same as above.

The reaction of the compound of Formula (34) with the compound ofFormula (35) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (3), in which X, is halogen,with the compound of Formula (2) in Reaction Formula 1.

The reaction converting the compound of Formula (36) to the compound ofFormula (5c) can be carried out under the same reaction conditions asthose for the reaction converting the compound of Formula (1a) to thecompound of Formula (1b) in Reaction Formula 2.

-   wherein R¹, R², R³, R⁴, R⁶, X_(A) and A¹ are the same as above.-   R¹² is hydrogen, lower alkyl, lower alkoxycarbonyl,    2,3-dihydrobenzo[b]furylcarbonyl, or benzoyl. R¹³ is lower    alkoxycarbonyl, 2,3-dihydrobenzo[b]furyl carbonyl, or benzoyl, and    A² is lower alkylene.

The reaction converting the compound of Formula (37) to the compound ofFormula (38) can be carried out under the same reaction conditions asthose for the reaction converting the compound of Formula (1f) to thecompound of Formula (1c) in Reaction Formula 6.

wherein R¹, R², R³, R⁴, R⁶, X_(A), R¹², A¹, and A² are the same asabove. R¹³ is 2,3-dihydrobenzo[b]furyl or phenyl.

The reaction of the compound of Formula (38) with the compound ofFormula (39) is performed under the same reaction conditions as thosefor the reaction of the compound of Formula (11) with the compound ofFormula (12) in Reaction Formula 10.

In addition, compounds in the form in which a solvate (for example, ahydrate, ethanolate, etc.) was added to the starting material compoundsand object compounds shown in each of the reaction formulae are includedin each of the formulae.

The compound of Formula (1) according to the present invention includesstereoisomers and optical isomers.

The starting material compounds and object compounds represented by eachof the reaction formulae can be used in an appropriate salt form.

Each of the object compounds obtained according to the above reactionformulae can be isolated and purified from the reaction mixture by, forexample, after cooling the reaction mixture, performing an isolationprocedure such as filtration, concentration, extraction, etc., toseparate a crude reaction product, and then subjecting the crudereaction product to a usual purification procedure such as columnchromatography, recrystallization, etc.

Among the compounds of the present invention, those having a basic groupor groups can easily form salts with common pharmaceutically acceptableacids. Examples of such acids include hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid and other inorganicacids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citricacid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acidand other organic acids, etc.

Among the compounds of the present invention, those having an acidicgroup or groups can easily form salts by reacting with pharmaceuticallyacceptable basic compounds. Examples of such basic compounds includesodium hydroxide, potassium hydroxide, calcium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.

The following is an explanation of pharmaceutical preparationscomprising the compound of the present invention as an activeingredient.

Such pharmaceutical preparations are obtained by formulating thecompound of the present invention into usual pharmaceuticalpreparations, using usually employed diluents or excipients such asfillers, extenders, binders, wetting agents, disintegrants, surfactants,lubricants, etc.

The form of such pharmaceutical preparations can be selected fromvarious forms according to the purpose of therapy. Typical examplesinclude tablets, pills, powders, solutions, suspensions, emulsions,granules, capsules, suppositories, injections (solutions, suspensions,etc.) and the like.

To form tablets, any of various known carriers can be used, including,for example, lactose, white sugar, sodium chloride, glucose, urea,starch, calcium carbonate, kaolin, crystalline cellulose and otherexcipients; water, ethanol, propanol, simple syrup, glucose solutions,starch solutions, gelatin solutions, carboxymethylcellulose, shellac,methylcellulose, potassium phosphate, polyvinylpyrrolidone and otherbinders; dry starch, sodium alginate, agar powder, laminaran powder,sodium hydrogencarbonate, calcium carbonate, fatty acid esters ofpolyoxyethylenesorbitan, sodium laurylsulfate, stearic acidmonoglyceride, starch, lactose and other disintegrants; white sugar,stearin, cacao butter, hydrogenated oils and other disintegrationinhibitors; quaternary ammonium base, sodium lauryl sulfate and otherabsorption promoters; glycerin, starch and other wetting agents; starch,lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents;purified talc, stearates, boric acid powder, polyethylene glycol andother lubricants; etc.

Such tablets may be coated with usual coating materials as required, toprepare, for example, sugar-coated tablets, gelatin-coated tablets,enteric-coated tablets, film-coated tablets, double- or multi-layeredtablets, etc.

To form pills, any of various known carriers can be used, including, forexample, glucose, lactose, starch, cacao butter, hydrogenated vegetableoils, kaolin, talc and other excipients; gum arabic powder, tragacanthpowder, gelatin, ethanol and other binders; laminaran, agar and otherdisintegrants; etc.

To form suppositories, any of various known carriers can be used,including, for example, polyethylene glycol, cacao butter, higheralcohols, esters of higher alcohols, gelatin, semisynthetic glycerides,etc.

To form an injection, a solution, emulsion or suspension is sterilizedand preferably made isotonic with blood. Any of various known widelyused diluents can be employed to prepare the solution, emulsion orsuspension. Examples of such diluents include water, ethanol, propyleneglycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,fatty acid esters of polyoxyethylene sorbitan, etc. In this case, thepharmaceutical preparation may contain sodium chloride, glucose orglycerin in an amount sufficient to prepare an isotonic solution, andmay contain usual solubilizers, buffers, analgesic agents, etc., andfurther, if necessary, coloring agents, preservatives, flavors,sweetening agents, etc., and/or other medicines.

The proportion of the compound of the present invention in thepharmaceutical preparation is not limited and can be suitably selectedfrom a wide range. It is usually preferable that the pharmaceuticalpreparation contain the compound of the present invention in aproportion of 1 to 70 wt. %.

The route of administration of the pharmaceutical preparation accordingto the present invention is not limited, and the preparation can beadministered by a route suitable for the form of the preparation, thepatient's age and sex, the conditions of the disease, and otherconditions.

For example, tablets, pills, solutions, suspensions, emulsions, granulesand capsules are administered orally.

Injections are intravenously administered singly or as mixed with usualinjection transfusions such as glucose solutions, amino acid solutionsor the like, or singly administered intramuscularly, intracutaneously,subcutaneously or intraperitoneally, as required. Suppositories areadministered intrarectally.

The dosage of the pharmaceutical preparation is suitably selectedaccording to the method of use, the patient's age and sex, the severityof the disease, and other conditions, and is usually about 0.001 toabout 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg bodyweight/day, in single or divided doses.

Since the dosage varies depending on various conditions, a dosagesmaller than the above range may be sufficient, or a dosage larger thanthe above range may be required.

When administered to the human body as a pharmaceutical, the compound ofthe present invention may be used concurrently with, or before or after,antithrombotics such as blood clotting inhibitors and antiplateletagents (e.g., warfarin, aspirin, etc.). Further, the present compoundmay be used concurrently with, or before or after, drugs for treatingchronic diseases, such as antihypertensive drugs (ACE inhibitors, betablockers, angiotensin II receptor antagonists), heart failure drugs(cardiotonic agents, diuretics), and diabetes treatment agents.

The compound of the present invention has potent blocking effects onhuman Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERGchannels. Thus, the compound of the invention has characteristics as anatrial-selective K⁺ channel-blocking agent.

Therefore, the compound of the invention can be used as apharmacologically active substance that is safer and provides a morepotent effect on the prolongation of the atrial refractory period thanconventional antiarrhythmic agents. The compound of the invention ispreferably used as a therapeutic agent for arrhythmia such as atrialfibrillation, atrial flutter, and atrial tachycardia (elimination ofarrhythmia and/or prevention of the occurrence of arrhythmia). Thecompound of the invention is particularly preferably used as atherapeutic agent for atrial fibrillation (defibrillation andmaintenance of sinus rhythm). The compound of the invention can also beused as a prophylactic agent for thromboembolism such as cerebralinfarction and as a therapeutic agent for heart failure.

The compound having potent blocking effects on both human Kv1.5 andhuman GIRK1/4 channels has more potent atrial refractory periodprolongation effects and is highly safe, compared to compoundsinhibiting either one of the channels. Furthermore, this compound hasgreater therapeutic effects on atrial fibrillation (defibrillation andmaintenance of sinus rhythm) than compounds inhibiting either one of thechannels. Therefore, the compound having potent blocking effects on boththe human Kv1.5 and human GIRK1/4 channels is particularly useful as atherapeutic agent for arrhythmia such as atrial fibrillation, atrialflutter, and atrial tachycardia (termination of arrhythmia and/orprevention of the occurrence of arrhythmia). This compound isparticularly useful as a therapeutic agent for atrial fibrillation(defibrillation and maintenance of sinus rhythm).

BEST MODE FOR CARRYING OUT THE INVENTION

The following Examples are intended to illustrate the present inventionin future detail.

REFERENCE EXAMPLE 1 Synthesis of ethylN-(5-methoxy-2-nitrophenyl)-N-methyl malonamate

Sodium hydride (60% in oil, 96 mg, 2.4 mmol) was suspended in 10 ml ofdimethylformamide (DMF).

N-Methyl-5-methoxy-2-nitroaniline (364 mg, 2 mmol) was added thereto at0° C., and stirring was conducted for 30 minutes at room temperature.Ethyl malonyl chloride (0.38 ml, 3 mmol) was added at 0° C. to thestirred mixture, and the reaction mixture was stirred at roomtemperature overnight. Water was added thereto, and extraction withethyl acetate was performed. The organic layer was dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1→1:2). The purified product was concentrated under reducedpressure to thereby obtain 554 mg (yield: 90%) of ethylN-(5-methoxy-2-nitrophenyl)-N-methyl malonamate as a yellow oil.

¹H-NMR (CDCl₃) δppm:

1.24 (3H, t, J=7.1 Hz), 3.15-3.17 (2H, m), 3.25 (3H, s), 3.92 (3H, s),4.13 (2H, q, J=7.1 Hz), 6.93 (1H, d, J=2.8 Hz), 7.02 (1H, dd, J=2.8 and9.2 Hz), 8.15 (1H, d, J=9.2 Hz).

REFERENCE EXAMPLE 2 Synthesis of ethylN-ethyl-N-(5-methoxy-2-nitrophenyl)malonamate

Using an appropriate starting material and following the procedure ofReference Example 1, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.11 (3H, t, J=7.2 Hz), 1.24 (3H, t, J=7.1 Hz), 3.11-3.25 (2H, m),3.39-3.46 (1H, m), 3.92 (3H, s), 3.98-4.17 (3H, m), 6.89 (1H, d, J=2.8Hz), 7.03 (1H, dd, J=9.2 and 2.8 Hz), 8.13 (1H, d, J=9.2 Hz).

REFERENCE EXAMPLE 3 Synthesis of ethylN-(2-amino-5-methoxyphenyl)-N-methyl malonamate

Palladium carbon (10%, 0.5 g) was added to an ethanol solution (150 ml)of ethyl N-(5-methoxy-2-nitrophenyl)-N-methyl malonamate (3.0 g, 10mmol), and catalytic reduction was conducted at room temperature andnormal pressure. The reaction mixture was filtered through Celite toremove the catalyst. The filtrate was concentrated under reducedpressure to thereby obtain 2.68 g (yield: quantitative) of ethylN-(2-amino-5-methoxyphenyl)-N-methyl malonamate as a yellow oil.

¹H-NMR (CDCl₃) δppm:

1.22 (3H, t, J=7.1 Hz), 3.19-3.27 (5H, m), 3.52-3.68 (2H, br), 3.74 (3H,s), 4.11 (2H, q, J=7.1 Hz), 6.62 (1H, d, J=2.7 Hz), 6.73 (1H, d, J=8.7Hz), 6.79 (1H, dd, J=2.7 and 8.7 Hz).

REFERENCE EXAMPLE 4 Synthesis of8-methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium ethoxide (204 mg, 3.0 mmol) was added to an ethanol solution (15ml) of ethyl N-(2-amino-5-methoxyphenyl)-N-methyl malonamate (266 mg,1.0 mmol), and stirred at 65° C. for 2.5 hours. The reaction mixture wascooled to room temperature, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(dichloromethane:methanol=1:0→10:1). The purified product wasconcentrated to dryness under reduced pressure to thereby obtain 176.3mg (yield: 80%) of8-methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as awhite powder.

¹H-NMR (CDCl₃) δppm:

3.36 (2H, s), 3.43 (3H, s), 3.84 (3H, s), 6.79-6.83 (1H, m), 7.06-7.09(1H, m), 8.72 (1H, br-s).

REFERENCE EXAMPLE 5 Synthesis of1-ethyl-8-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Palladium carbon (10%, 1.1 g) was added to an ethanol solution (250 ml)of ethyl N-ethyl-N-(5-methoxy-2-nitrophenyl)malonamate (21.05 g, 67.8mmol), and cooled in an ice water bath. Catalytic reduction wasconducted at about room temperature. Celite filtration was conducted toremove the catalyst, and the filtrate was concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (THF) (200 ml).Sodium ethoxide (6.9 g, 102 mmol) was added thereto, and then heatingwas conducted under reflux for 15 minutes. The reaction mixture wascooled to room temperature, and the precipitated insoluble matter wascollected by filtration. The filtrate was concentrated under reducedpressure. Water was added to the residue and the collected insolublematter, and the mixture was neutralized with hydrochloric acid.Extraction with ethyl acetate was then performed. The organic layer waswashed with a saturated sodium chloride aqueous solution, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was recrystallized from ethanol to thereby obtain 7.9 g (yield:50%) of 1-ethyl-8-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione asa white powder. The mother liquor was then concentrated, and the residuewas purified using a silica gel flash column (n-hexane:ethylacetate=1:1→0:1) to thereby obtain 2.9 g of object compound.

¹H-NMR (CDCl₃) δppm:

1.19 (3H, t, J=7.1 Hz), 3.33 (2H, s), 3.78-3.84 (1H, m), 3.84 (3H, s),4.13-4.25 (1H, m), 6.82 (1H, dd, J=8.8 and 2.7 Hz), 6.87 (1H, d, J=2.7Hz), 7.09 (1H, d, J=8.8 Hz), 8.82 (1H, br-s).

REFERENCE EXAMPLE 6 Synthesis of1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium hydride (60% in oil, 44 mg, 1.1 mmol) was suspended indimethylformamide (DMF) (8 ml), and cooled in an ice water bath to 0° C.8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg,1.0 mmol) was added to the suspension at the same temperature, andstirred at 0° C. for 1 hour. Ethyl iodide (187 mg, 1.2 mmol) was addedto the mixture and stirred at room temperature overnight. Water wasadded to the reaction mixture, and extraction with ethyl acetate wasperformed. The organic layer was dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purifiedproduct was concentrated to dryness under reduced pressure to therebyobtain 190.2 mg (yield: 77%) of1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a yellow solid.

¹H-NMR (CDCl₃) δppm:

1.11 (3H, t, J=7.1 Hz), 3.31-3.32 (2H, m), 3.40 (3H, s), 3.59-3.68 (1H,m), 3.85 (3H, s), 4.18-4.30 (1H, m), 6.78 (1H, d, J=2.8 Hz), 6.84 (1H,dd, J=9.0 and 2.8 Hz), 7.26 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 7 Synthesis of1,5-diethyl-7-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 6, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.04-1.14 (6H, m), 3.28 (2H, s), 3.50-3.64 (2H, m), 3.85 (3H, s),4.35-4.47 (2H, m), 6.83-6.88 (2H, m), 7.25-7.27 (1H, m).

REFERENCE EXAMPLE 8 Synthesis of7-methoxy-5-methyl-1-propyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 6, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.76 (3H, t, J=7.3 Hz), 1.35-1.62 (2H, m), 3.32 (2H, s), 3.40 (3H, s),3.33-3.51 (1H, m), 3.49 (3H, s), 4.21-4.38 (1H, m), 6.78 (1H, d, J=2.8Hz), 6.84 (1H, dd, J=9.0 and 2.8 Hz), 7.25 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 9 Synthesis of1-isobutyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 6, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.69 (3H, d, J=6.7 Hz), 0.77 (3H, d, J=6.7 Hz), 1.56-1.90 (1H, m), 3.24(1H, dd, J=13.6 and 5.9 Hz), 3.33 (2H, s), 3.40 (3H, s), 3.85 (3H, s),4.32 (1H, dd, J=13.6 and 9.0 Hz), 6.78 (1H, d, J=2.8 Hz), 6.84 (1H, dd,J=9.0 and 2.9 Hz), 7.24 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 10 Synthesis of7-methoxy-5-methyl-1-(3-methylbutyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 6, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.80 (3H, d, J=6.3 Hz), 0.86(3H, d, J=6.3 Hz), 1.22-1.53 (3H, m), 3.32(2H, s), 3.39 (3H, s), 3.36-3.62 (1H, m), 3.85 (3H, s), 4.31-4.48 (1H,m), 6.78 (1H, d, J=2.8 Hz), 6.85 (1H, dd, J=8.8 and 2.8 Hz), 7.25 (1H,d, J=8.8 Hz).

REFERENCE EXAMPLE 11 Synthesis of7-methoxy-5-methyl-1-(3-methylbut-2-enyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 6, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.63 (6H, s), 3.32-3.34 (2H, m), 3.38 (3H, s), 3.84 (3H, s), 4.33 (1H,dd, J=13.6 and 6.2 Hz), 4.51 (1H, dd, J=13.6 and 6.9 Hz), 5.14-5.19 (1H,m), 6.76 (1H, d, J=2.8 Hz), 6.81 (1H, dd, J=9.0 and 2.8 Hz), 7.27 (1H,d, J=9.0 Hz).

REFERENCE EXAMPLE 12 Synthesis of1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium hydride (60% in oil, 76 mg, 1.9 mmol) was suspended in DMF (8ml).1-Ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(190 mg, 0.76 mmol) was added thereto at 0° C., and stirring wasconducted at the same temperature for 1 hour. Methyl iodide (0.19 ml,3.1 mmol) was added to the mixture, and stirred at room temperature for3 days. Water was added to the reaction mixture, and extraction withethyl acetate was performed. The organic layer was dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate). Thepurified product was concentrated to dryness under reduced pressure tothereby obtain 169 mg (yield: 80%) of1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a yellow powder.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.40 (3H, s),3.65-3.76 (1H, m), 3.85 (3H, s), 4.12-4.24 (1H, m), 6.73 (1H, d, J=2.8Hz), 6.83 (1H, dd, J=9.0 and 2.8 Hz), 7.22 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 13 Synthesis of7-methoxy-3,3,5-trimethyl-1-propyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 12, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.76 (3H, t, J=7.3 Hz), 0.85 (3H, s), 1.52 (3H, s), 1.38-1.68 (2H, m),3.41 (3H, s), 3.42-3.58 (1H, m), 3.85 (3H, s), 4.19-4.31 (1H, m), 6.72(1H, d, J=2.8 Hz), 6.81 (1H, dd, J=9.0 and 2.8 Hz), 7.20 (1H, d, J=9.0Hz).

REFERENCE EXAMPLE 14 Synthesis of7-methoxy-3,3,5-trimethyl-1-(3-methylbutyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 12, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.82 (3H, d, J=6.2 Hz), 0.85 (3H, s), 0.86 (3H, d, J=6.2 Hz), 1.30-1.49(3H, m), 1.52 (3H, s), 3.40 (3H, s), 3.49-3.62 (1H, m), 3.85 (3H, s),4.21-4.36 (1H, m), 6.71 (1H, d, J=2.8 Hz), 6.80 (1H, dd, J=9.0 and 2.8Hz), 7.20 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 15 Synthesis of1,5-diethyl-7-methoxy-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 12, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.06-1.18 (6H, m), 1.51 (3H, s), 3.56-3.83 (2H, m), 3.85(3H, s), 4.29-4.42 (2H, m), 6.79-6.86 (2H, m), 7.21 (1H, d, J=8.9 Hz).

REFERENCE EXAMPLE 16 Synthesis of1,3-diethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 12, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, t, J=7.3 Hz), 1.06 (3H, t, J=7.0 Hz), 1.94-2.05 (2H, m), 2.97(1H, t, J=6.9 Hz), 3.40 (3H, s), 3.55-3.66 (1H, m), 3.86 (3H, s),4.20-4.33 (1H, m), 6.79 (1H, d, J=2.8 Hz), 6.84-6.88 (1H, m), 7.26-7.29(1H, m).

REFERENCE EXAMPLE 17 Synthesis of3,3-diethyl-7-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Diethylmalonyl dichloride (0.95 ml, 5.5 mmol) was added to adichloromethane solution (20 ml) of 4-methoxy-o-phenylenediamine (691mg, 5 mmol) and triethylamine (1.7 ml, 12.5 mmol) at 0° C., and stirredat room temperature overnight. Water was added to the reaction mixture,and extraction with dichloromethane was performed. The organic layer waswashed with a saturated sodium chloride aqueous solution, dried oversodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=9:1→1:1). The purified product was concentrated to dryness underreduced pressure to thereby obtain 452.3 mg (yield: 34%) of3,3-diethyl-7-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as ayellow oil.

¹H-NMR (CDCl₃) δppm:

1.10 (6H, t, J=7.5 Hz), 1.86 (4H, q, J=7.5 Hz), 3.76 (3H, s), 4.18 (2H,br), 6.30 (1H, d, J=2.7 Hz), 6.35 (1H, dd, J=8.7 and 2.7 Hz), 7.23 (1H,d, J=8.7 Hz).

REFERENCE EXAMPLE 18 Synthesis of3,3-diethyl-7-methoxy-1,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium hydride (60% in oil, 170 mg, 4.3 mmol) was suspended in DMF (15ml). 3,3-Diethyl-7-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(452 mg, 1.7 mmol) was added thereto at 0° C., and stirring wasconducted at the same temperature for 1 hour. Methyl iodide (0.42 ml,6.8 mmol) was added to the mixture, and stirred at room temperature for3 days. Water was added to the reaction mixture and extraction withethyl acetate was performed. The organic layer was dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1→1:1). The purified product was concentrated to dryness underreduced pressure to thereby obtain 373 mg (yield: 76%) of3,3-diethyl-7-methoxy-1,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a white powder.

¹H-NMR (CDCl₃) δppm:

0.56 (3H, t, J=7.4 Hz), 1.02 (3H, t, J=7.3 Hz), 1.20-1.31 (2H, m), 2.15(2H, q, J=7.3 Hz), 3.38 (3H, s), 3.41 (3H, s), 3.85 (3H, s), 6.71 (1H,d, J=2.8 Hz), 6.81 (1H, dd, J=9.0 and 2.8 Hz), 7.14 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 19 Synthesis of7-methoxy-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium hydride (60% in oil, 128 mg, 3.2 mmol) was suspended in DMF (10ml). 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (176mg, 0.8 mmol) was added thereto at 0° C., and stirring was conducted atthe same temperature for 1 hour. Methyl iodide (0.25 ml, 4.0 mmol) wasadded to the mixture, and stirred at room temperature overnight. Waterwas added to the reaction mixture, and extraction with ethyl acetate wasperformed. The organic layer was washed with water, dried over sodiumsulfate, and concentrated under reduced pressure. The residue wasrecrystallized from n-hexane to thereby obtain 161.6 mg (yield: 77%) of7-methoxy-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a white powder.

¹H-NMR (CDCl₃) δppm:

0.87 (3H, s), 1.54 (3H, s), 3.40 (3H, s), 3.42 (3H, s), 3.84 (3H, s),6.73 (1H, s), 6.84 (1H, d, J=8.9 Hz), 7.14 (1H, d, J=8.9 Hz).

REFERENCE EXAMPLE 20 Synthesis of5-ethyl-7-methoxy-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 19, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.38 (3H, s),3.75-3.82 (1H, m), 3.84 (3H, s), 4.12-4.19 (1H, m), 6.80-6.85 (2H, m),7.16 (1H, dd, J=8.6 and 0.5 Hz).

REFERENCE EXAMPLE 21 Synthesis of1,3,3,5-tetraethyl-7-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 19, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.56 (3H, t, J=7.4 Hz), 0.98 (3H, t, J=7.4 Hz), 1.07-1.26 (6H, m),2.10-2.17 (2H, m), 3.59-3.74 (2H, m), 3.85 (3H, s), 4.24-4.32 (2H, m),6.78-6.85 (2H, m), 7.20 (1H, d, J=8.9 Hz).

REFERENCE EXAMPLE 22 Synthesis of1,3,3-triethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 19, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.57 (3H, t, J=7.4 Hz), 1.00 (3H, t, J=7.3 Hz), 1.16 (3H, t, J=7.2 Hz),1.21-1.29 (2H, m), 2.10-2.19 (2H, m), 3.40 (3H, s), 3.72-3.83 (1H, m),3.85 (3H, s), 4.06-4.14 (1H, m), 6.71 (1H, d, J=2.8 Hz), 6.82 (1H, dd,J=9.0 and 2.8 Hz), 7.21 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 23 Synthesis of1,3,5-triethyl-7-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 19, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, t, J=7.5 Hz), 0.88-1.11 (6H, m), 2.92-2.97 (1H, m), 3.50-3.65(2H, m), 3.86 (3H, s), 4.12 (2H, q, J=7.2 Hz), 4.38-4.45 (2H, m),6.84-6.89 (2H, m), 7.25-7.28 (1H, m).

REFERENCE EXAMPLE 24 Synthesis of1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

A 1.0 M boron tribromide/dichloromethane solution (1.22 ml) was added toa dichloromethane solution (3 ml) of1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(169 mg, 1.0 mmol) at 0° C., and stirred at room temperature overnight.Water and methanol were added to the reaction mixture and extractionwith the mixture solvent (dichloromethane:methanol=10:1) was performed.The organic layer was dried over anhydrous sodium sulfate, andconcentrated to dryness under reduced pressure to thereby obtain 156.4mg (yield: 98%) of1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a white powder.

¹H-NMR (CDCl₃) δppm:

0.90 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.55 (3H, s), 3.41 (3H, s),3.66-3.78 (1H, m), 4.12-4.23 (1H, m), 6.79 (1H, d, J=2.7 Hz), 6.84 (1H,dd, J=8.8 and 2.7 Hz), 6.88 (1H, d, J=2.7 Hz), 7.18 (1H, d, J=8.8 Hz).

REFERENCE EXAMPLE 25 Synthesis of3,3-diethyl-7-hydroxy-1,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.55 (3H, t, J=7.3 Hz), 1.00 (3H, t, J=7.3 Hz), 1.15-1.29 (2H, m), 2.12(2H, q, J=7.3 Hz), 3.37 (3H, s), 3.38 (3H, s), 6.69 (1H, d, J=2.7 Hz),6.76 (1H, dd, J=8.8 and 2.7 Hz), 7.06 (1H, d, J=8.8 Hz).

REFERENCE EXAMPLE 26 Synthesis of1,3,3-triethyl-7-hydroxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.59 (3H, t, J=7.3 Hz), 1.01 (3H, t, J=7.3 Hz), 1.18 (3H, t, J=7.1 Hz),1.21-1.34 (2H, m), 2.13-2.24 (2H, m), 3.40 (3H, s), 3.71-3.82 (1H, m),4.05-4.16 (1H, m), 6.78 (1H, d, J=2.7 Hz), 6.84 (1H, dd, J=8.8 and 2.7Hz), 7.04 (1H, br-s), 7.17 (1H, d, J=8.8 Hz).

REFERENCE EXAMPLE 27 Synthesis of1,3-diethyl-7-hydroxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (3H, t, J=7.4 Hz), 1.07 (3H, t, J=7.1 Hz), 1.95-2.05 (2H, m), 3.00(1H, t, J=6.9 Hz), 3.39 (3H, s), 3.58-3.64 (1H, m), 4.22-4.29 (1H, m),5.87 (1H, br-s), 6.80-6.84 (2H, m), 7.21-7.24 (1H, m).

REFERENCE EXAMPLE 28 Synthesis of1,3-diethyl-7-hydroxy-3,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.64 (3H, t, J=7.3 Hz), 1.11-1.26 (5H, m), 1.54 (3H, s), 3.40 (3H, s),3.70-3.82 (1H, m), 4.06-4.17 (1H, m), 6.39 (1H, br-s), 6.75-6.83 (2H,m), 7.17-7.24 (1H, d, J=8.8 Hz).

REFERENCE EXAMPLE 29 Synthesis of5-ethyl-7-hydroxy-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.88 (3H, s), 1.20 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.38 (3H, s),3.73-3.84 (1H, m), 4.07-4.19 (1H, m), 6.76-6.81 (2H, m), 7.11 (1H, d,J=8.7 Hz).

REFERENCE EXAMPLE 30 Synthesis of7-hydroxy-3,3,5-trimethyl-1-propyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CD₃OD) δppm:

0.74 (3H, t, J=7.4 Hz), 0.85 (3H, s), 1.43 (3H, s), 1.38-1.61 (2H, m),3.36 (3H, s), 3.53-3.61 (1H, m), 4.21-4.29 (1H, m), 6.76-6.82 (2H, m),7.26 (1H, d, J=8.5 Hz).

REFERENCE EXAMPLE 31 Synthesis of7-hydroxy-3,3,5-trimethyl-1-(3-methylbutyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CD₃OD) δppm:

0.79 (3H, d, J=6.1 Hz), 0.85 (3H, s), 0.85 (3H, d, J=6.1 Hz), 1.26-1.40(3H, m), 1.42 (3H, s), 3.35 (3H, s), 3.56-3.63 (1H, m), 4.34-4.41 (1H,m), 6.76-6.82 (2H, m), 7.28 (1H, d, J=8.7 Hz).

REFERENCE EXAMPLE 32 Synthesis of1,3,3,5-tetraethyl-7-hydroxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.58 (3H, t, J=7.4 Hz), 0.98 (3H, t, J=7.3 Hz), 1.08-1.29 (8H, m),2.12-2.19 (2H, m), 3.57-3.76 (2H, m), 4.20-4.34 (2H, m), 6.09 (1H,br-s), 6.78-6.82 (2H, m), 7.14-7.17 (1H, m).

REFERENCE EXAMPLE 33 Synthesis of1,5-diethyl-7-hydroxy-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (3H, s), 1.08-1.17 (6H, m), 1.54 (3H, s), 3.57-3.73 (2H, m),4.27-4.39 (2H, m), 6.85-6.87 (2H, m), 7.15-7.18 (1H, m).

REFERENCE EXAMPLE 34 Synthesis of1,3,5-triethyl-7-hydroxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, t, J=7.4 Hz), 1.02-1.12 (6H, m), 1.95-2.19 (2H, m), 3.03 (1H,t, J=6.9 Hz), 3.51-3.70 (2H, m), 4.33-4.46 (2H, m), 6.89-6.93 (2H, m),7.23 (1H, d, J=8.5 Hz), 7.57 (1H, s).

REFERENCE EXAMPLE 35 Synthesis of7-hydroxy-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.90 (3H, s), 1.49 (3H, s), 3.39 (3H, s), 3.40 (3H, s), 6.73 (1H, d,J=2.7 Hz), 6.80 (1H, dd, J=8.9 and 2.7 Hz), 7.13 (1H, d, J=8.9 Hz).

REFERENCE EXAMPLE 36 Synthesis of7-hydroxy-1-isobutyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 24, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.69 (3H, d, J=6.7 Hz), 0.75 (3H, d, J=6.7 Hz), 0.87 (3H, s), 1.53 (3H,s), 1.72-1.91 (1H, m), 3.24 (1H, dd, J=6.3 and 13.5 Hz), 3.40 (3H, s),4.35 (1H, dd, J=8.6 and 13.5 Hz), 6.72-6.79 (2H, m), 7.13 (1H, d, J=8.6Hz).

REFERENCE EXAMPLE 37 Synthesis of7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(1.85 g, 7.1 mmol) and potassium carbonate (1.2 g, 8.5 mmol) were addedto 50% water-containing acetonitrile (40 ml), and dissolved by heatingto 70° C. 1-Bromo-3-chloropropane (2.1 ml, 21 mmol) was added thereto,and heating was conducted under reflux for 6 hours. The reaction mixturewas cooled to room temperature. Water was added, and extraction withethyl acetate was performed. The organic layer was dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1→1:1). The purified product was concentrated to dryness underreduced pressure to thereby obtain 2.18 g (yield: 91%) of7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a colorless oil.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.21-2.38 (2H, m),3.40 (3H, s), 3.63-3.89 (4H, m), 4.10-4.26 (2H, m), 6.74 (1H, d, J=2.8Hz), 6.83 (1H, dd, J=2.8 and 9.0 Hz), 7.21 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 38 Synthesis of7-(3-chloropropoxy)-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 37, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.88 (3H, s), 1.53 (3H, s), 2.20-2.32 (2H, m), 3.40 (3H, s), 3.42 (3H,s), 3.77 (2H, t, J=6.1 Hz), 4.15 (2H, t, J=5.8 Hz), 6.74 (1H, d, J=2.7Hz), 6.83 (1H, dd, J=2.7 and 9.0 Hz), 7.15 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 39 Synthesis of1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

7-(3-Chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(2.18 g, 6.4 mmol) and sodium iodide (4.8 g, 32 mmol) were added toacetone (50 ml), and heated under reflux for 8.5 hours. The reactionmixture was cooled to room temperature, water was added, and extractionwith ethyl acetate was performed. The organic layer was dried oversodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1). The purified product was concentrated under reducedpressure to thereby obtain 2.76 g (yield: 100%) of1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a colorless oil.

¹H-NMR (CDCl₃) δppm:

0.87 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.26-2.34 (2H, m),3.39 (2H, t, J=6.6 Hz), 3.65-3.76 (1H, m), 3.41 (3H, s), 4.07 (2H, t,J=5.8 Hz), 4.12-4.24 (1H, m), 6.74 (1H, d, J=2.8 Hz), 6.83 (1H, dd,J=9.0 and 2.8 Hz), 7.22 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 40 Synthesis of7-(3-iodopropoxy)-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofReference Example 39, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.88 (3H, s), 1.54 (3H, s), 2.22-2.34 (2H, m), 3.39 (2H, t, J=6.6 Hz),3.40 (3H, s), 3.42 (3H, s), 4.07 (2H, t, J=5.8 Hz), 6.74 (1H, d, J=2.8Hz), 6.83 (1H, dd, J=2.8 and 9.0 Hz), 7.15 (1H, d, J=9.0 Hz).

REFERENCE EXAMPLE 41 Synthesis of(2-pyridin-3-ylethyl)pyridin-4-ylmethylamine

4-Pyridinecarbaldehyde (5.36 g, 50 mmol) and 3-(2-aminoethyl)pyridine(6.5 ml, 50 mmol) were added to methanol (100 ml), and stirred at roomtemperature for 7 hours. The resulting mixture was cooled to 0° C.Sodium borohydride (2.8 g, 74 mmol) was added to the mixture, andstirred at 0° C. for 1 hour. Water was then added to the reactionmixture to distill the methanol off under reduced pressure. The residuewas extracted with dichloromethane. The organic layer was washed with asaturated sodium chloride aqueous solution, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (ethylacetate:methanol=95:5→85:5). The purified product was concentrated underreduced pressure to thereby obtain 10.03 g (yield: 94%) of(2-pyridin-3-ylethyl)pyridin-4-ylmethylamine as a colorless oil.

¹H-NMR (CDCl₃) δppm:

2.79-2.98 (4H, m), 3.82 (2H, s), 7.21-7.25 (3H, m), 7.51-7.55 (1H, m),8.47-8.50 (2H, m), 8.52-8.54 (2H, m)

REFERENCE EXAMPLE 42 Synthesis of(2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(tetrahydropyran-2-yloxy)propyl]amine

Sodium iodide (1.5 g, 10 mmol) was added to a DMF solution (20 ml) of2-(3-bromopropoxy)tetrahydropyran (0.85 ml, 5 mmol), and stirred at 70°C. for 7 hours. The reaction mixture was cooled to room temperature.(2-Pyridin-3-ylethyl)pyridin-4-ylmethylamine (1.28 g, 6 mmol) andN-ethyl diisopropylamine (1.3 ml, 7.5 mmol) were then added to thereaction mixture and stirred at room temperature overnight. Water wasadded to the reaction mixture, and extraction with ethyl acetate wasperformed. The organic layer was washed with water, and a saturatedsodium chloride aqueous solution, in this order. The organic layer wasdried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate:methanol=20:1→4:1). The purified product was concentratedunder reduced pressure to thereby obtain 236 mg (yield: 13%) of(2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(tetrahydropyran-2-yloxy)propyl]amineas a colorless oil.

¹H-NMR (CDCl₃) δppm:

1.40-1.92 (8H, m), 2.52-2.83 (6H, m), 3.30-3.56 (2H, m), 3.62 (2H, s),3.66-3.90 (2H, m), 4.51-4.53 (1H, m), 7.16 (2H, d, J=6.0 Hz), 7.19 (1H,d, J=4.8 Hz), 7.42 (1H, d, J=6.6 Hz), 8.41-8.49 (4H, m)

REFERENCE EXAMPLE 43 Synthesis of3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol

A 2N-hydrogen chloride methanol solution (1.2 ml) was added to amethanol solution (4 ml) of(2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(tetrahydropyran-2-yloxy)propyl]amine(236 mg, 0.66 mmol), and stirred at room temperature overnight. A2N-hydrogen chloride methanol solution (0.5 ml) was added to themixture, and stirred at 50° C. for 3 hours. Triethylamine (0.64 ml) wasthen added to the reaction mixture, and concentrated under reducedpressure. The residue was purified by basic silica gel columnchromatography (dichloromethane). The purified product was concentratedunder reduced pressure to thereby obtain 186.3 mg (yield: quantitative)of 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol as anorange oil.

¹H-NMR (CDCl₃) δppm:

1.70-1.86 (2H, m), 2.67-2.78 (4H, m), 2.81 (2H, t, J=6.0 Hz), 3.65 (2H,s), 3.72 (2H, t, J=5.5 Hz), 7.18 (2H, d, J=5.9 Hz), 7.21 (1H, d, J=4.9Hz), 7.42 (1H, dt, J=1.8 and 7.8 Hz), 8.42-8.54 (2H, m), 8.54 (2H, d,J=5.9 Hz).

REFERENCE EXAMPLE 44 Synthesis of6-[2-(tetrahydropyran-2-yloxy)ethyl]-6H-furo[2,3-c]pyridin-7-one

Sodium hydride (60% in oil, 138 mg, 3.5 mmol) was suspended in DMF (10ml). A DMF solution (5 ml) of 6H-furo[2,3-c]pyridin-7-one (310 mg, 2.3mmol) was added thereto at 0° C., and stirring was conducted at the sametemperature for 1 hour. A DMF solution (5 ml) of2-(2-iodoethoxy)tetrahydropyran (1175 mg, 4.6 mmol) was added thereto,and stirring was conducted at room temperature overnight. Water wasadded to the reaction mixture and extraction with ethyl acetate wasperformed. The organic layer was washed with water, dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1→1:1). The purified product was concentrated under reducedpressure to thereby obtain 450 mg (yield: 74%) of6-[2-(tetrahydropyran-2-yloxy)ethyl]-6H-furo[2,3-c]pyridin-7-one as ayellow oil.

¹H-NMR (CDCl₃) δppm:

1.46-1.81 (6H, m), 3.40-3.47 (1H, m), 3.63-3.79 (2H, m), 4.00-4.07 (1H,m), 4.16-4.24 (1H, m), 4.34-4.41 (1H, m), 4.54 (1H, t, J=3.1 Hz), 6.43(1H, d, J=7.0 Hz), 6.65 (1H, d, J=1.9 Hz), 7.26 (1H, d, J=7.0 Hz), 7.73(1H, d, J=1.9 Hz).

REFERENCE EXAMPLE 45 Synthesis of7-methyl-2-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-isoquinolin-1-one

Using an appropriate starting material and following the procedure ofReference Example 44, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.39-1.88 (6H, m), 2.49 (3H, s), 3.33-3.48 (1H, m), 3.61-3.81 (2H, m),4.00-4.21 (2H, m), 4.28-4.39 (1H, m), 4.53-4.56 (1H, m), 6.43 (1H, d,J=7.4 Hz), 7.15 (1H, d, J=7.4 Hz), 7.41 (1H, d, J=8.1 Hz), 7.45 (1H, dd,J=1.7 and 8.1 Hz), 8.23 (1H, s).

REFERENCE EXAMPLE 46 Synthesis of6-(2-hydroxyethyl)-6H-furo[2,3-c]pyridin-7-one

Pyridinium p-toluenesulfonate (0.21 g, 0.85 mmol) was added to amethanol solution (20 ml) of6-[2-(tetrahydropyran-2-yloxy)ethyl]-6H-furo[2,3-c]pyridin-7-one (0.45g, 1.7 mmol), and stirred at room temperature for 2 days. An aqueoussodium hydrogen carbonate solution was added to the reaction mixture,and extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate, and concentrated under reduced pressure.Diethyl ether was added to the residue to precipitate crystals. Thecrystals were collected by filtration and dried to thereby obtain 223 mg(yield: 73%) of 6-(2-hydroxyethyl)-6H-furo[2,3-c]pyridin-7-one as awhite powder.

¹H-NMR (CDCl₃) δppm:

3.15 (1H, t, J=5.3 Hz), 3.96-4.01 (2H, m), 4.25 (2H, t, J=5.3 Hz), 6.49(1H, d, J=7.0 Hz), 6.66 (1H, d, J=2.0 Hz), 7.18 (1H, d, J=7.0 Hz), 7.75(1H, d, J=2.0 Hz).

REFERENCE EXAMPLE 47 Synthesis of2-(2-hydroxyethyl)-7-methyl-2H-isoquinolin-1-one

Using an appropriate starting material and following the procedure ofReference Example 46, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

2.48 (3H, s), 3.29 (1H, t, J=5.2 Hz), 3.96-4.01 (2H, m), 4.16-4.19 (2H,m), 6.49 (1H, d, J=7.3 Hz), 7.05 (1H, d, J=7.3 Hz), 7.41 (1H, d, J=8.1Hz), 7.46 (1H, dd, J=1.7 and 8.1 Hz), 8.20 (1H, d, J=1.7 Hz).

REFERENCE EXAMPLE 48 Synthesis of2-nitro-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide

2-Nitrobenzenesulfonyl chloride (22.1 g, 0.10 mol) was added to adichloromethane solution (400 ml) of 3-aminopropanol (8.2 g, 0.11 mol)and triethylamine (21 ml, 0.15 mol) at 0° C., and stirred at roomtemperature overnight. Water was added to the reaction mixture andextraction with dichloromethane was performed. The organic layer wasdried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was dissolved in dichloromethane (400 ml), and3,4-dihydro-2H-pyrane (9.3 g, 0.11 mol) and p-toluenesulfonic acid (1.9g, 0.01 mol) were added thereto. Stirring was conducted at roomtemperature overnight. A 1N-sodium hydroxide aqueous solution was addedto the reaction mixture, and extraction with dichloromethane wasperformed. The organic layer was washed with water, dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1→1:2). The purified product was concentrated under reducedpressure to thereby obtain 27.56 g (yield: 80%) of2-nitro-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide as apale brown oil.

¹H-NMR (CDCl₃) δppm:

1.40-1.93 (6H, m), 3.12-3.38 (2H, m), 3.38-3.58 (2H, m), 3.75-3.92 (2H,m), 4.11-4.17 (1H, m), 4.51-4.54 (1H, m), 5.85-5.93 (1H, m), 7.63-7.79(2H, m), 7.79-7.92 (1H, m), 8.07-8.20 (1H, m).

REFERENCE EXAMPLE 49 Synthesis of2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide

Triphenylphosphine (393 mg, 1.5 mmol) and azodicarboxylic aciddi-tert-butyl ester (345 mg, 1.5 mmol) were added to a tetrahydrofuran(THF) solution (10 ml) of 6-(2-hydroxyethyl)-6H-furo[2,3-c]pyridin-7-one(179 mg, 1.0 mmol) and2-nitro-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide (413 mg,1.2 mmol), and stirred overnight. The resulting reaction mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=1:1→0:1). The purifiedproduct was concentrated to dryness under reduced pressure to therebyobtain 286 mg (yield: 57%) of2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamideas a white amorphous solid.

¹H-NMR (CDCl₃) δppm:

1.37-1.91 (8H, m), 3.25-3.59 (4H, m), 3.61-3.88 (4H, m), 4.27 (2H, t,J=6.5 Hz), 4.45-4.49 (1H, m), 6.43 (1H, d, J=7.0 Hz), 6.64 (1H, s), 7.19(1H, d, J=7.0 Hz), 7.49-7.69 (3H, m), 7.72 (1H, s), 7.92-8.02 (1H, m).

REFERENCE EXAMPLE 50 Synthesis of2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofReference Example 49, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.40-1.91 (8H, m), 3.21-3.61 (4H, m), 3.61-3.86 (4H, m), 4.21 (2H, t,J=6.6 Hz), 4.45-4.48 (1H, m), 6.45 (1H, d, J=7.3 Hz), 7.14 (1H, d, J=7.3Hz), 7.38-7.79 (6H, m), 7.91-8.01 (1H, m), 8.34 (1H, d, J=7.5 Hz).

REFERENCE EXAMPLE 51 Synthesis of2-nitro-N-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofReference Example 49, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.44-1.98 (8H, m), 3.01 (2H, t, J=6.6 Hz), 3.28-3.82 (12H, m), 4.46-4.49(1H, m), 7.18 (1H, d, J=7.6 Hz), 7.29-7.72 (5H, m), 7.98-8.07 (2H, m).

REFERENCE EXAMPLE 52 Synthesis ofN-(3-hydroxypropyl)-2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofReference Example 46, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.73-1.87 (2H, m), 3.51 (2H, t, J=6.9 Hz), 3.63 (2H, t, J=5.7 Hz), 3.71(2H, t, J=6.8 Hz), 4.27 (2H, t, J=6.8 Hz), 6.46 (1H, d, J=7.0 Hz), 6.65(1H, d, J=1.9 Hz), 7.20 (1H, d, J=7.0 Hz), 7.50-7.69 (3H, m), 7.73 (1H,d, J=1.9 Hz), 7.92-8.01 (1H, m).

REFERENCE EXAMPLE 53 Synthesis ofN-(3-hydroxypropyl)-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofReference Example 46, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.72-1.89 (2H, m), 3.54 (2H, t, J=6.7 Hz), 3.65 (2H, t, J=5.5 Hz), 3.72(2H, t, J=6.7 Hz), 4.23 (2H, t, J=6.8 Hz), 6.49 (1H, d, J=7.3 Hz), 7.15(1H, d, J=7.3 Hz), 7.42-7.70 (6H, m), 7.90-8.00 (1H, m), 8.34 (1H, d,J=7.9 Hz).

REFERENCE EXAMPLE 54 Synthesis ofN-(3-hydroxypropyl)-2-nitro-N-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofReference Example 46, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.75-2.05 (2H, m), 3.01 (2H, t, J=6.2 Hz), 3.46-3.88 (10H, m), 7.18 (1H,d, J=7.6 Hz), 7.34 (1H, d, J=7.7 Hz), 7.39-7.42 (1H,m), 7.57-7.70 (3H,m), 7.97-8.06 (2H, m).

REFERENCE EXAMPLE 55 Synthesis of3-{(2-nitrobenzenesulfonyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propylmethanesulfonate

Methanesulfonyl chloride (0.14 ml, 1.8 mmol) was added to a THF solution(30 ml) ofN-(3-hydroxypropyl)-2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]benzenesulfonamide(644 mg, 1.5 mmol) and triethylamine (0.34 ml, 2.3 mmol), and stirred atroom temperature overnight. Water was added to the reaction mixture, andextraction with dichloromethane was performed. The organic layer wasdried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate:methanol=1:0→0:1). The purified product was concentratedto dryness under reduced pressure to thereby obtain 480 mg (yield: 64%)of3-{(2-nitrobenzenesulfonyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propylmethanesulfonate as a white amorphous solid.

¹H-NMR (CDCl₃) δppm:

1.95-2.05 (2H, m), 3.04 (3H, s), 3.50 (2H, t, J=7.1 Hz), 3.70 (2H, t,J=6.7 Hz), 4.18 (2H, t, J=5.8 Hz), 4.26 (2H, t, J=6.7 Hz), 6.47 (1H, d,J=7.0 Hz), 6.66 (1H, d, J=1.9 Hz), 7.19 (1H, d, J=7.0 Hz), 7.50-7.74(4H, m), 7.94-8.02 (1H, m).

REFERENCE EXAMPLE 56 Synthesis of3-{(2-nitrobenzenesulfonyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propylmethanesulfonate

Using an appropriate starting material and following the procedure ofReference Example 55, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.98-2.09 (2H, m), 3.01 (3H, s), 3.52 (2H, t, J=6.9 Hz), 3.71 (2H, t,J=6.6 Hz), 4.17 (2H, t, J=5.8 Hz), 4.21 (2H, t, J=6.9 Hz), 6.47 (1H, d,J=7.4 Hz), 7.13 (1H, d, J=7.4 Hz), 7.45-7.70 (6H, m), 7.90-8.00 (1H, m),8.33 (1H, d, J=7.7 Hz).

REFERENCE EXAMPLE 57 Synthesis of3-{(2-nitrobenzenesulfonyl)-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]amino}propylmethanesulfonate

Using an appropriate starting material and following the procedure ofReference Example 55, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

2.04-2.19 (2H, m), 3.01 (2H, t, J=6.7 Hz), 3.02 (3H, s), 3.39-3.48 (6H,m), 3.75 (2H, t, J=7.2 Hz), 4.26 (2H, t, J=5.9 Hz), 7.17 (1H, d, J=7.4Hz), 7.28-7.45 (2H, m), 7.60-7.74 (3H, m), 7.96-8.04 (2H, m).

REFERENCE EXAMPLE 58 Synthesis ofN-(3-iodopropyl)-2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]benzenesulfonamide

3-{(2-Nitrobenzenesulfonyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propylmethanesulfonate (480 mg, 0.96 mmol) and sodium iodide (720 mg, 4.8mmol) were added to acetone (20 ml), and heated under reflux for 5hours. The reaction mixture was cooled to room temperature, water wasadded, and extraction with dichloromethane was performed. The organiclayer was dried over sodium sulfate, and concentrated under reducedpressure to thereby obtain 474 mg (yield: 93%) ofN-(3-iodopropyl)-2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]benzenesulfonamideas a yellow amorphous solid.

¹H-NMR (DMSO-D₆) δppm:

1.89-2.02 (2H, m), 3.12 (2H, t, J=6.9 Hz), 3.42 (2H, t, J=7.3 Hz), 3.66(2H, t, J=5.8 Hz), 4.15 (2H, t, J=5.9 Hz), 6.49 (1H, d, J=7.0 Hz), 6.84(1H, d, J=1.9 Hz), 7.37 (1H, d, J=7.0 _(Hz))_(,) 7.69-7.81 (2H, m),7.87-7.99 (2H, m), 8.09 (1H, d, J=1.9 Hz).

REFERENCE EXAMPLE 59 Synthesis ofN-(3-iodopropyl)-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofReference Example 58, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

2.02-2.18 (2H, m), 3.06 (2H, t, J=7.0 Hz), 3.44 (2H, t, J=7.2 Hz), 3.72(2H, t, J=6.5 Hz), 4.21 (2H, t, J=6.5 Hz), 6.46 (1H, d, J=7.3 Hz), 7.13(1H, d, J=7.3 Hz), 7.41-7.70 (6H, m), 7.95-8.06 (1H, m), 8.34 (1H, d,J=7.9 Hz).

REFERENCE EXAMPLE 60 Synthesis ofN-(3-iodopropyl)-2-nitro-N-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofReference Example 58, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

2.03-2.20 (2H, m), 3.02 (2H, t, J=6.6 Hz), 3.12 (2H, t, J=6.6 Hz), 3.50(2H, t, J=7.1 Hz), 3.56-3.70 (4H, m), 3.76 (2H, t, J=7.0 Hz), 7.17 (1H,d, J=7.5 Hz), 7.28-7.45 (2H,m), 7.60-7.70 (3H, m), 8.00-8.11 (2H, m).

REFERENCE EXAMPLE 61 Synthesis of tert-butylmethyl-[2-(2-nitrobenzenesulfonylamino)ethyl]carbamate

2-Nitrobenzenesulfonyl chloride (4.9 g, 22 mmol) was added to adichloromethane solution (100 ml) oftest-butyl(2-aminoethyl)methylcarbamate (3.5 g, 20 mmol) andtriethylamine (3.3 ml, 24 mmol) at 0° C., and stirred at roomtemperature overnight. Water was added to the reaction mixture, andextraction with dichloromethane was performed. The organic layer wasdried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:2→2:3). The purified product was concentratedunder reduced pressure to thereby obtain 5.06 g (yield: 70%) oftert-butyl methyl-[2-(2-nitrobenzenesulfonylamino)ethyl]carbamate as ayellow oil.

¹H-NMR (CDCl₃) δppm:

1.45 (9H, s), 2.84 (3H, s), 3.26-3.41 (4H, m), 7.68-7.79 (2H, m),7.79-7.90 (1H, m), 8.09-8.19 (1H, m).

REFERENCE EXAMPLE 62 Synthesis of2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide

Using an appropriate starting material and following the procedure ofReference Example 61, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

2.88 (2H, t, J=7.1 Hz), 3.41 (2H, q, J=7.1 Hz), 5.44 (1H, t, J=5.4 Hz),7.18-7.22 (1H,m), 7.50 (1H,dt, J=7.8 and1.8 Hz), 7.71-7.77 (2H, m),7.82-7.88 (1H, m), 8.07-8.12 (1H, m), 8.35 (1H, d, J=1.8 Hz), 8.45 (1H,dd, J=4.8 and 1.8 Hz).

EXAMPLE 1 Synthesis of7-(3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Potassium carbonate (2.99 g, 21.6 mmol) and N-(3-bromopropyl)phthalimide(2.32 g, 8.65 mmol) were added to a DMF solution (50 ml) of1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(1.89 g, 7.2 mmol), and stirred at room temperature overnight. Water wasadded to the reaction mixture, and extraction with ethyl acetate wasperformed. The organic layer was washed with water and a saturatedsodium chloride aqueous solution, in this order. The organic layer wasdried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1→3:7). The purified product was concentratedto dryness under reduced pressure to thereby obtain 2.70 g (yield: 83%)of7-(3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a white powder.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.13 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.18-2.24 (2H, m),3.33 (3H, s), 3.63-3.75 (1H, m), 3.93 (2H, t, J=6.8 Hz), 4.06 (2H, t,J=5.9 Hz), 4.10-4.10 (1H, m), 6.59 (1H, d, J=2.8 Hz), 6.73 (1H, dd,J=9.0 and 2.8 Hz), 7.16 (1H, d, J=9.0 Hz), 7.72-7.76 (2H, m), 7.82-7.88(2H, m).

EXAMPLE 2 Synthesis of7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Hydrazine hydrate (1.17 ml, 24 mmol) was added to a methanol solution(60 ml) of7-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(2.70 g, 6.0 mmol), and stirred while heating under reflux for 2 hours.The reaction mixture was concentrated under reduced pressure. A1N-sodium hydroxide aqueous solution was added to the residue, andstirred for 30 minutes, and extraction with dichloromethane wasperformed. The organic layer was washed with water and a saturatedsodium chloride aqueous solution, in this order. The organic layer wasdried over anhydrous magnesium sulfate, and concentrated under reducedpressure to thereby obtain 1.48 g (yield: 77%) of7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a colorless oil.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.90-2.00 (2H, m),2.94 (2H, t, J=6.8 Hz), 3.40 (3H, s), 3.66-3.76 (1H, m), 4.08 (2H, t,J=6.2 Hz), 4.11-4.21 (1H, m), 6.73 (1H, d, J=2.8 Hz), 6.82 (1H, dd,J=9.0 and 2.8 Hz), 7.20 (1H, d, J=9.0 Hz).

EXAMPLE 3 Synthesis of7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionehydrochloride

A 4N-hydrogen chloride ethyl acetate solution (0.42 ml) was added to anethyl acetate solution (3 ml) of7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (264 mg), and stirred at room temperature for 30minutes. The reaction mixture was concentrated to dryness under reducedpressure to thereby obtain 0.22 g of7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride as a white amorphous solid.

¹H-NMR (DMSO-D₆) δppm:

0.77 (3H, s), 1.01 (3H, t, J=6.6 Hz), 1.33 (3H, s), 1.92-2.38 (4H, m),3.33 (3H, s), 3.67-4.20 (6H, m), 6.95-7.00 (2H, m), 7.42 (1H, d, J=8.8Hz), 8.28 (1H, br-s).

EXAMPLE 4 Synthesis ofN-(3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl)-2-nitrobenzenesulfonamide

Triethylamine (0.8 ml, 5.7 mmol) was added to a dichloromethane solution(50 ml) of7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(1.22 g, 3.8 mmol) and ice-cooled. o-Nitrobenzenesulfonyl chloride (1.03g, 4.2 mmol) was added to the resulting mixture, and stirred at roomtemperature for 2 hours. Water was added to the reaction mixture, andextraction with dichloromethane was performed. The organic layer waswashed with water and a saturated sodium chloride aqueous solution, inthis order, then dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=1:1→0:1): The purifiedproduct was concentrated to dryness under reduced pressure to therebyobtain 1.86 g (yield: 97%) ofN-(3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl)-2-nitrobenzenesulfonamideas a white amorphous solid.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.05-2.13 (2H, m),3.34-3.40 (2H, m), 3.40 (3H, s), 3.65-3.77 (1H, m), 4.07-4.21 (3H, m),5.76 (1H, t, J=5.9 Hz), 6.77 (1H, d, J=2.7 Hz), 6.82 (1H, dd, J=8.9 and2.8 Hz), 7.21 (1H, d, J=9.0 Hz), 7.73-7.79 (2H, m), 7.85-7.89 (1H, m),8.14-8.18 (1H, m).

EXAMPLE 5 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(5.3 mmol) was added to a methanol solution (100 ml) of3-(2-aminoethyl)pyridine (3.3 g, 26.7 mmol), and stirred at 50° C. for 9hours. The reaction mixture was cooled to room temperature, andconcentrated under reduced pressure. Water was added to the residue, andextraction with dichloromethane was performed. The organic layer wasdried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(dichloromethane:methanol=20:1→10:1). The purified product wasconcentrated under reduced pressure, and the residue was purified bybasic silica gel column chromatography (ethyl acetate:methanol=1:0→10:1)again. The purified product was concentrated under reduced pressure tothereby obtain 1.57 g (yield: 70%) of1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a yellow oil.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.93-2.00 (2H,m),2.80-2.96 (6H, m), 3.39 (3H, s), 3.66-3.73 (1H, m), 4.04 (2H, t, J=6.1Hz), 4.14-4.21 (1H, m), 6.70 (1H, d, J=2.8 Hz), 6.78 (1H, dd, J=9.0 and2.0 Hz), 7.17-7.24 (2H, m), 7.54 (1H, dt, J=7.8 and 1.9 Hz), 8.46 (1H,dd, J=4.8 and 1.6 Hz), 8.49 (1H, d, J=2.0 Hz).

EXAMPLE 6 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1, 4]diazepine-2,4-dionedihydrochloride

A 4N-hydrogen chloride ethyl acetate solution (0.37 ml) was added to anethyl acetate solution (10 ml) of1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(207 mg, 0.49 mmol), and stirred for 30 minutes at room temperature. Theprecipitated insoluble matter was collected by filtration, washed withethyl acetate, and dried to thereby obtain 208 mg (yield: 85%) of1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride as a pale yellow amorphous solid.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.14-2.20 (2H, m),3.10 (2H, br-s), 3.25-3.33 (6H, m), 3.61-3.73 (1H, m), 3.99-4.18 (4H,m), 6.92-6.99 (2H, m), 7.42 (1H, d, J=8.9 Hz), 7.94-7.89 (1H, m), 8.46(1H, d, J=8.0 Hz), 8.80 (1H, dd, J=5.5 and 1.0 Hz), 8.90 (1H, d, J=1.0Hz), 9.46 (2H, br-s).

EXAMPLE 7 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

4-Pyridinecarbaldehyde (1.18 ml, 12.5 mmol) and a catalytic amount ofacetic acid were added to a 1,2-dichloroethane solution (40 ml) of1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(4.44 g, 10.5 mmol), and stirred for 30 minutes. Sodiumtriacetoxyhydroborate (3.33 g, 15.7 mmol) was added to the resultingmixture, and stirred at room temperature overnight. The reaction mixturewas diluted with dichloromethane, washed with water and a saturatedsodium chloride aqueous solution in this order, then dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel flash chromatography (ethylacetate:methanol=1:0→9:1). The purified product was concentrated underreduced pressure to thereby obtain 4.73 g (yield: 88%) of1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as apale yellow oil.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.0 Hz), 1.52 (3H, s), 1.87-1.95 (2H, m),2.67-2.80 (6H, m), 3.40 (3H, s), 3.66-3.77 (3H, m), 3.89 (2H, t, J=6.0Hz), 4.09-4.21 (1H, m), 6.63 (1H, d, J=2.7 Hz), 6.72 (1H, dd, J=9.0 and2.7 Hz), 7.12-7.22 (4H, m), 7.42 (1H, dt, J=7.8 and 1.9 Hz), 8.42-8.46(4H, m).

EXAMPLE 8 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Triphenylphosphine (186 mg, 0.71 mmol) and di-tert-butylazodicarboxylate (163 mg, 0.71 mmol) were added to a tetrahydrofuran(THF) solution (5 ml) of1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(156 mg, 0.59 mmol) and3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol (161 mg,0.59 mmol), and stirred overnight. The reaction mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate:methanol=1:0→4:1), and the purifiedproduct was concentrated under reduced pressure. A 4N-hydrogen chlorideethyl acetate solution (0.29 ml) was added to the residue (ethyl acetatesolution), stirred at room temperature for 30 minutes, and concentratedto dryness under reduced pressure to thereby obtain 206 mg (yield: 56%)of1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride as a white amorphous solid.

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.22-2.41 (2H, m),3.15-3.53 (6H, m), 3.33 (3H, s), 3.64-3.71 (1H, m), 4.07-4.14 (3H, m),4.62-4.86 (2H, m), 6.88-6.94 (2H, m), 7.42 (1H, d, J=8.8 Hz), 8.03 (1H,dd, J=8.0 and 5.7 Hz), 8.27-8.42 (2H, m), 8.54 (1H, d, J=8.0 Hz), 8.84(1H, d, J=4.8 Hz), 8.94-9.02 (3H, m).

EXAMPLE 9 Synthesis of 1-isobutyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

N,N,N′,N′-Tetramethylazodicarboxamide(TMAD) (189 mg, 1.1 mmol) andtri-n-butyl phosphine (0.28 ml, 1.1 mmol) were added to a THF solution(5 ml) of7-hydroxy-1-isobutyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(213 mg, 0.73 mmol) and3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol (199 mg,0.73 mmol), and stirred at room temperature overnight. Water was addedto the reaction mixture, and extraction with dichloromethane wasperformed. The organic layer was dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate:methanol=20:1→10:1). Thepurified product was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography(dichloromethane:methanol=40:1→10:1) again. The purified product wasconcentrated under reduced pressure. A 4N-hydrogen chloride ethylacetate solution (0.57 ml) was added to the residue (ethyl acetatesolution), stirred at room temperature for 30 minutes, and concentratedto dryness under reduced pressure to thereby obtain 480 mg (yield:quantitative) of1-isobutyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride as a white amorphous solid.

¹H-NMR (DMSO-D₆) δppm:

0.58 (3H, d, J=6.6 Hz), 0.71 (3H, d, J=6.6 Hz), 0.75 (3H, s), 1.33 (3H,s), 1.51-1.78 (2H, m), 2.19-2.38 (2H, m), 3.00-3.48 (7H, m), 3.34 (3H,s), 4.02-4.28 (2H, m), 4.38-4.59 (2H, m), 6.86-6.94 (2H, m), 7.45 (1H,d, J=9.0 Hz), 7.63-7.67 (1H, m), 7.87 (2H, d, J=5.2 Hz), 8.07 (1H, d,J=7.9 Hz), 8.62 (1H, d, J=1.3 Hz), 8.66-8.78 (3H, m).

EXAMPLE 10 Synthesis of3,3,5-trimethyl-1-propyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 9, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.64 (3H, t, J=7.4 Hz), 0.75 (3H, s), 1.32 (3H, s), 1.28-1.51 (2H, m),2.18-2.41 (2H, m), 3.09-3.61 (7H, m), 3.32 (3H, s), 4.02-4.26 (3H, m),4.47-4.82 (2H, m), 6.82-6.97 (2H, m), 7.42 (1H, d, J=8.8 Hz), 7.92-8.03(1H, m), 8.08-8.31 (2H, m), 8.41-8.50 (1H, m), 8.82 (1H, d, J=5.6 Hz),8.83-8.98 (3H, m).

EXAMPLE 11 Synthesis of3,3,5-trimethyl-1-(3-methylbutyl)-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 9, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.68-1.80 (15H, m), 2.28-2.48 (2H, m), 3.19-3.40 (2H, m), 3.31 (3H, s),3.40-3.64 (5H, m), 4.03-4.18 (2H, m), 4.18-4.33 (1H, m), 4.70-4.92 (2H,m), 6.87-6.99 (2H, m), 7.44 (1H, d, J=8.9 Hz), 8.00-8.09 (1H, m),8.38-8.50 (2H, m), 8.51-8.62 (1H, m), 8.86 (1H, d, J=5.5 Hz), 8.94-9.08(3H, m).

EXAMPLE 12 Synthesis of5-ethyl-1,3,3-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 9, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.03 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.21-2.41 (2H, m),3.15-3.32 (2H, m), 3.28 (3H, s), 3.32-3.58 (4H, m), 3.64-3.82 (1H, m),4.01-4.18 (3H, m), 4.59-4.82 (2H, m), 6.86-7.00 (2H, m), 7.38 (1H, d,J=8.9 Hz), 8.02 (1H, dd, J=5.7 and 8.0 Hz), 8.32 (2H, s), 8.53 (1H, d,J=8.1 Hz), 8.83 (1H, d, J=5.2 Hz), 8.90-8.99 (3H, m).

EXAMPLE 13 Synthesis of1,3,3,5-tetraethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 9, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.47 (3H, t, J=7.1 Hz), 0.76-1.80 (13H, m), 1.80-2.00 (2H, m), 2.25-2.44(2H, m), 3.22-3.40 (2H, m), 3.40-3.58 (2H, m), 3.58-3.79 (2H, m),4.02-4.30 (4H, m), 4.70-4.92 (2H, m), 6.93 (2H, dd, J=2.5 and 9.0 Hz),6.99 (1H, d, J=2.5 Hz), 7.44 (1H, d, J=9.0 Hz), 8.06 (1H, dd, J=5.8 and7.9 Hz), 8.49 (1H, s), 8.60 (1H, d, J=8.1 Hz), 8.86 (1H, d, J=5.5 Hz),8.96-9.09 (3H, m).

EXAMPLE 14 Synthesis of1,5-diethyl-3,3-dimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 9, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.73 (3H, s), 0.79-1.01 (6H, m), 1.31 (3H, s), 2.20-2.45 (2H, m),3.18-3.38 (2H, m), 3.38-3.52 (2H, m), 3.52-3.79 (2H, m), 4.09-4.16 (2H,m), 4.16-4.35 (2H, m), 4.63-4.89 (2H, m), 6.92 (1H, dd, J=2.6 and 9.0Hz), 6.99 (1H, d, J=2.6 Hz), 7.43 (1H, d, J=9.0 Hz), 8.02 (1H, dd, J=5.7and 8.0 Hz), 8.34 (2H, s), 8.55 (1H, d, J=8.0 Hz), 8.84 (1H, d, J=5.4Hz), 8.94-8.97 (3H, m).

EXAMPLE 15 Synthesis of1,3,5-triethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 9, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.62-1.80 (11H, m), 2.22-2.41 (2H, m), 2.81-3.00 (1H, m), 3.12-3.37 (2H,m), 3.37-3.55 (4H, m), 3.55-3.85 (2H, m), 4.08-4.19 (2H, m), 4.19-4.38(2H, m), 4.62-4.88 (2H, m), 6.92 (1H, d, J=9.1 Hz), 7.05 (1H, s), 7.50(1H, d, J=9.1 Hz), 8.03 (1H, dd, J=5.9 and 7.9 Hz), 8.37 (2H, s), 8.56(1H, d, J=8.0 Hz), 8.84 (1H, d, J=5.5 Hz), 8.92-9.02 (3H, m).

EXAMPLE 16 Synthesis of2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide

2-Nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide (1.8 g, 5.8 mmol) andpotassium carbonate (1.0 g, 7.2 mmol) were added to a DMF solution (30ml) of7-(3-iodopropoxy)-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(2.0 g, 4.8 mmol) and stirred at room temperature overnight. Thereaction mixture was added to ice water, and extraction with ethylacetate was performed. The organic layer was washed with water, driedover anhydrous sodium sulfate, concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:2→ethyl acetate→ethyl acetate:methanol=20:1). The purifiedproduct was concentrated to dryness under reduced pressure to therebyobtain 2.29 g (yield: 80%) of2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamideas a yellow amorphous solid.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.53 (3H, s), 2.02-2.12 (2H, m), 2.91 (2H, t, J=8.1 Hz),3.39 (3H, s), 3.41 (3H, s), 3.57 (2H, t, J=8.4 Hz), 3.60 (2H, t, J=7.4Hz), 4.01 (2H, t, J=5.9 Hz), 6.71 (1H, d, J=2.7 Hz), 6.77 (1H, d, J=8.8Hz), 7.14 (1H, d, J=8.9 Hz), 7.18-7.24 (1H, m), 7.48-7.64 (4H, m), 8.00(1H, d, J=9.2 Hz), 8.41 (1H, d, J=2.1 Hz), 8.45 (1H, d, J=4.8 Hz).

EXAMPLE 17 Synthesis of2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamidehydrochloride

A 4N-hydrogen chloride ethyl acetate solution (0.57 ml) was added to anethyl acetate solution (1 ml) of2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide(236 mg), and stirred at room temperature for 1 minute. The precipitatedinsoluble matter was collected by filtration, washed with ethyl acetate,and dried to thereby obtain 163 mg (yield: 65%) of2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamidehydrochloride as a white powder.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.33 (3H, s), 1.89-2.08 (2H, m), 3.10 (2H, t, J=7.0 Hz),3.30 (3H, s), 3.33 (3H, s), 3.55 (2H, t, J=7.6 Hz), 3.69 (2H, t, J=6.8Hz), 4.00 (2H, t, J=6.0 Hz), 6.82-6.95 (2H, m), 7.34 (1H, d, J=8.8 Hz),7.76-7.96 (4H, m), 8.03 (1H, d, J=7.4 Hz), 8.40 (1H, d, J=7.8 Hz), 8.75(1H, d, J=5.3 Hz), 8.85 (1H, s).

EXAMPLE 18 Synthesis of1,3,3,5-tetramethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Lithium hydroxide (0.36 g, 15 mmol) and thioglycolic acid (0.48 ml, 6.9mmol) were added to a DMF solution (20 ml) of2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide(2.05 g, 3.4 mmol), and stirred at room temperature for 3 days. Thereaction mixture was added to ice water, and extracted with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethylacetate:methanol=20:1→dichloromethane:methanol=10:1→4:1). The purifiedproduct was concentrated under reduced pressure to thereby obtain 1.13 g(yield: 81%) of1,3,3,5-tetramethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a yellow oil.

¹H-NMR (CDCl₃) δppm:

0.87 (3H, s), 1.53 (3H, s), 1.92-2.02 (2H, m), 2.78-2.90 (4H, m), 2.93(2H, t, J=6.5 Hz), 3.39 (3H, s), 3.41 (3H, s), 4.04 (2H, t, J=6.2 Hz),6.71 (1H, d, J=2.7 Hz), 6.78 (1H, dd, J=2.7 and 8.9 Hz), 7.13 (1H, d,J=9.0 Hz), 7.16-7.25 (1H, m), 7.54 (1H, d, J=7.8 Hz), 8.46 (1H, dd,J=1.6 and 4.8 Hz), 8.49 (1H, d, J=1.6 Hz).

EXAMPLE 19 Synthesis of1,3,3,5-tetramethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 8, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.33 (3H, s), 2.18-2.40 (2H, m), 3.10-3.64 (6H, m), 3.30(3H, s), 3.33 (3H, s), 3.97-4.14 (2H, m), 4.40-4.72 (2H, m), 6.81-6.92(2H, m), 7.36 (1H, d, J=8.6 Hz), 7.73-8.02 (3H, m), 8.28 (1H, d, J=6.4Hz), 8.68-8.82 (4H, m).

EXAMPLE 20 Synthesis of3,3-diethyl-1,5-dimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 8, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.54 (3H, t, J=7.5 Hz), 1.01 (3H, t, J=7.5 Hz), 1.12-1.31 (4H, m),2.09-2.24 (2H, m), 2.99-3.41 (6H, m), 3.38 (3H, s), 3.41 (3H, s),3.97-4.08 (2H, m), 4.40-4.88 (2H, m), 6.67 (1H, d, J=2.6 Hz), 6.74 (1H,dd, J=9.0 and 2.6 Hz), 7.14 (1H, d, J=9.0 Hz), 7.51-7.62 (1H, m), 7.70(2H, d, J=5.3 Hz), 7.96 (1H, d, J=7.1 Hz), 8.61 (1H, d, J=4.7 Hz), 8.70(2H, d, J=5.3 Hz), 8.89 (1H, s).

EXAMPLE 21 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide

Potassium carbonate (0.22 g, 1.6 mmol) was added to a DMF solution (10ml) ofN-(3-iodopropyl)-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide(0.57 g, 1.05 mmol) and1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.33 g, 1.26 mmol), and stirred at room temperature overnight. Thereaction mixture was added to ice water, and extraction with ethylacetate was performed. The organic layer was washed with 1N-sodiumhydroxide aqueous solution and water, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1→0:1). The purified product was concentrated to dryness underreduced pressure to thereby obtain 0.49 g (yield: 69%) ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamideas a white amorphous solid.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.14 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.08-2.14 (2H, m),3.39 (3H, s), 3.62 (2H, t, J=7.4 Hz), 3.66-3.77 (3H, m), 3.94 (2H, t,J=5.8 Hz), 4.13-4.22 (1H, m), 4.24 (2H, t, J=6.7 Hz), 6.46 (1H, d, J=7.3Hz), 6.67 (1H, d, J=2.7 Hz), 6.72 (1H, dd, J=8.9 and 2.7 Hz), 7.12-7.19(2H, m), 7.47-7.67 (6H, m), 7.95-7.98 (1H, m), 8.35 (1H, d, J=7.5 Hz).

EXAMPLE 22 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[2-(1-oxo-1H-isoquinolin-2-yl)ethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.14 (3H, t, J=7.0 Hz), 1.52 (3H, s), 1.92-2.00 (2H, m),2.87 (2H, t, J=6.7 Hz), 3.06 (2H, t, J=6.2 Hz), 3.38 (3H, s), 3.63-3.74(1H, m), 4.02 (2H, t, J=6.1 Hz), 4.09-4.23 (3H, m), 6.46 (1H, d, J=7.3Hz), 6.69 (1H, d, J=2.7 Hz), 6.74 (1H, dd, J=9.0 and 2.7 Hz), 7.10-7.16(2H, m), 7.46-7.51 (2H, m), 7.64 (1H, t, J=8.1 Hz), 8.41 (1H, d, J=8.2Hz).

EXAMPLE 23 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.74 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.01-2.39 (2H, m),2.89-3.51 (2H, m), 3.30 (3H, s), 3.61-3.73 (1H, m), 3.89-4.12 (5H, m),4.19-4.77 (4H, m), 6.67 (1H, d, J=7.0 Hz), 6.71-6.90 (2H, m), 7.37 (1H,d, J=9.0 Hz), 7.50-7.54 (2H, m), 7.66-7.76 (2H, m), 8.20 (1H, d, J=8.0Hz), 7.87-8.13 (2H, m), 8.60-8.96 (2H, m).

EXAMPLE 24 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder (Ethyl Acetate)

Melting point 119.8-121.6° C.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.53 (3H, s), 1.87-1.96 (2H, m),2.70-2.74 (2H, m), 2.83-2.93 (2H, m), 3.36 (3H, s), 3.36-3.74 (3H, m),3.86 (2H, t, J=6.0 Hz), 4.10 (2H, t, J=6.1 Hz), 4.12-4.21 (1H, m), 6.41(1H, d, J=7.3 Hz), 6.58-6.62 (2H, m), 6.98 (1H, d, J=7.3 Hz), 7.08-7.17(3H, m), 7.47-7.52 (2H, m), 7.66 (1H, td, J=7.5 and 1.7 Hz), 8.27 (2H,dd, J=4.4 and 1.6 Hz), 8.59 (1H, dt, J=8.1 and 0.7 Hz).

EXAMPLE 25 Synthesis of2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofExample 21, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, s), 1.53 (3H, s), 2.03-2.15 (2H, m), 3.39 (3H, s), 3.42 (3H,s), 3.59 (2H, t, J=7.4 Hz), 3.73 (2H, t, J=6.9 Hz), 3.94 (2H, t, J=5.8Hz), 4.29 (2H, t, J=6.7 Hz), 6.45 (1H, d, J=7.0 Hz), 6.64 (1H, d, J=2.0Hz), 6.69-6.75 (2H, m), 7.12 (1H, d, J=8.8 Hz), 7.19 (1H, d, J=7. 0 Hz),7.56-7.66 (3H, m), 7.73 (1H, d, J=1. 9 Hz), 7.98-8.02 (1H, m).

EXAMPLE 26 Synthesis of1,3,3,5-tetramethyl-7-{3-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.53 (3H, s), 1.90-2.02 (2H, m), 2.87 (2H, t, J=6.7 Hz),3.07 (2H, t, J=6.2 Hz), 3.39 (3H, s), 3.41 (3H, s), 4.03 (2H, t, J=6.1Hz), 4.20 (2H, t, J=6.5 Hz), 6.45 (1H, d, J=7.0 Hz), 6.65 (1H, d, J=2.0Hz), 6.72 (1H, d, J=2.7 Hz), 6.78 (1H, dd, J=2.7 and 8.9 Hz), 7.12 (1H,d, J=8.9 Hz), 7.17 (1H, d, J=7.0 Hz), 7.74 (1H, d, J=2.0 Hz).

EXAMPLE 27 Synthesis of1,3,3,5-tetramethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.33 (3H, s), 1.89-2.32 (2H, m), 2.89-3.51 (6H, m), 3.30(3H, s), 3.33 (3H, s), 3.91-4.12 (2H, m), 4.22-4.61 (2H, m), 6.62 (1H,d, J=6.5 Hz), 6.72-6.98 (3H, m), 7.35 (1H, d, J=8.9 Hz), 7.56 (1H, d,J=7.0 Hz), 8.08 (2H, br-s), 8.13 (1H, s), 8.81 (2H, br-s).

EXAMPLE 28 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofExample 21, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.06-2.13 (2H, m),3.40 (3H, s), 3.57-3.75 (5H, m), 3.94 (2H, t, J=5.8 Hz), 4.11-4.20 (1H,m), 4.29 (2H, t, J=6.9 Hz), 6.45 (1H, d, J=7.0 Hz), 6.64 (1H, d, J=2.0Hz), 6.70-6.76 (2H, m), 7.18 (1H, d, J=8.9 Hz), 7.20 (1H, d, J=7.0 Hz),7.55-7.66 (3H, m), 7.74 (1H, d, J=2.0 Hz), 7.99-8.02 (1H, m).

EXAMPLE 29 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.92-2.01 (2H, m),2.86 (2H, t, J=6.8 Hz), 3.05 (2H, t, J=6.2 Hz), 3.39 (3H, s), 3.66-3.75(1H, m), 4.02 (2H, t, J=6.1 Hz), 4.12-4.24 (3H, m), 6.43 (1H, d, J=7.0Hz), 6.64 (1H, d, J=2.0 Hz), 6.71 (1H, d, J=2.8 Hz), 6.78 (1H, dd, J=9.0and 2.8 Hz), 7.14 (1H, d, J=7.0 Hz), 7.18 (1H, d, J=9.0 Hz), 7.73 (1H,d, J=2.0 Hz).

EXAMPLE 30 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder (Ethyl Acetate-n-Hexane)

Melting point 80.7-82.8° C.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.89-1.97 (2H, m),2.73 (2H, t, J=6.8 Hz), 2.87 (2H, t, J=4.9 Hz), 3.40 (3H, s), 3.66-3.77(3H, m), 3.91 (2H, t, J=6.1 Hz), 4.09-4.22 (3H, m), 6.37 (1H, d, J=7.0Hz), 6.64-6.72 (3H, m), 6.99 (1H, d, J=7.0 Hz), 7.09 (2H, d, J=5.9 Hz),7.19 (1H, d, J=8.9 Hz), 7.75 (1H, d, J=2.0 Hz), 8.33 (2H, dd, J=4.5 and1.5 Hz).

EXAMPLE 31 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 3, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.98-2.20 (2H, m),2.92-3.40 (4H, m), 3.31 (3H, s), 3.63-3.71 (1H, m), 3.99-4.12 (4H, m),4.22-4.66 (3H, m), 6.62 (1H, d, J=6.7 Hz), 6.82-6.90 (3H, m), 7.39 (1H,d, J=9.0 Hz), 7.55 (1H, d, J=6.8 Hz), 7.89-8.19 (3H, m), 8.65-8.94 (2H,m).

EXAMPLE 32 Synthesis of2-nitro-N-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofExample 21, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, s), 1.53 (3H, s), 2.10-2.20 (2H, m), 2.95-3.07 (2H, m), 3.39(3H, s), 3.41 (3H, s), 3.55-3.69 (6H, m), 3.79 (2H, t, J=6.9 Hz), 3.99(2H, t, J=5.9 Hz), 6.65-6.77 (2H, m), 7.11 (1H, d, J=8.8 Hz), 7.18 (1H,d, J=7.8 Hz), 7.30-7.49 (2H, m), 7.58-7.69 (3H, m), 7.98-8.08 (2H, m).

EXAMPLE 33 Synthesis of1,3,3,5-tetramethyl-7-{3-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.53 (3H, s), 1.92-2.02 (2H, m), 2.87-3.02 (6H, m), 3.38(3H, s), 3.40 (3H, s), 3.62 (2H, t, J=6.4 Hz), 3.72 (2H, t, J=6.5 Hz),4.06 (2H, t, J=6.1 Hz), 6.72 (1H, d, J=2.7 Hz), 6.79 (1H, dd, J=2.7 and9.0 Hz), 7.10 (1H, d, J=8.9 Hz), 7.17 (1H, d, J=7.4 Hz), 7.29-7.43 (2H,m), 8.05 (1H, d, J=7.6 Hz).

EXAMPLE 34 Synthesis of1,3,3,5-tetramethyl-7-(3-{[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.33 (3H, s), 2.20-2.41 (2H, m), 2.98-3.08 (2H, m),3.16-3.45 (4H, m), 3.29 (3H, s), 3.33 (3H, s), 3.53-3.71 (2H, m),3.82-4.01 (2H, m), 4.03-4.20 (2H, m), 4.55-4.89 (2H, m), 6.81-6.97 (2H,m), 7.28-7.40 (3H, m), 7.42-7.54 (1H, m), 7.87 (1H, d, J=7.6 Hz), 8.28(2H, d, J=4.9 Hz), 8.94 (2H, d, J=5.6 Hz).

EXAMPLE 35 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-nitro-N-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofExample 21, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.14 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.10-2.24 (2H, m),3.01 (2H, t, J=6.5 Hz), 3.39 (3H, s), 3.59-3.87 (9H, m), 3.99 (2H, t,J=5.9 Hz), 4.08-4.23 (1H, m), 6.69 (1H, d., J=2.9 Hz), 6.74 (1H, dd,J=2.7 and 8.8 Hz), 7.17 (2H, d, J=9.0 Hz), 7.29-7.48 (2H, m), 7.57-7.69(3H, m), 8.00-8.05 (2H, m).

EXAMPLE 36 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, s), 1.14 (3H, t, J=7.0 Hz), 1.52 (3H, s), 1.91-2.06 (2H, m),2.82-3.02 (6H, m), 3.38 (3H, s), 3.53-3.78 (5H, m), 4.06 (2H, t, J=6.1Hz), 4.09-4.25 (1H, m), 6.72 (1H, d, J=2.7 Hz), 6.78 (1H, dd, J=2.7 and9.0 Hz), 7.16 (2H, d, J=8.9 Hz), 7.28-7.48 (2H, m), 8.05 (1H, d, J=7.6Hz).

EXAMPLE 37 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.22-2.43 (2H, m),2.98-3.10 (2H, m), 3.20-3.49 (4H, m), 3.32 (3H, s), 3.57-3.75 (3H, m),3.90-4.08 (3H, m), 4.08-4.20 (2H, m), 4.65-4.90 (2H, m), 6.80-6.97 (2H,m), 7.28-7.45 (3H, m), 7.45-7.55 (1H, m), 7.87 (1H, d, J=7.6 Hz), 8.38(2H, d, J=5.7 Hz), 8.99 (2H, d, J=6.1 Hz).

EXAMPLE 38 Synthesis of2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofExample 21, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, s), 1.53 (3H, s), 1.99-2.15 (2H, m), 3.39 (3H, s), 3.41 (3H,s), 3.61 (2H, t, J=6.9 Hz), 3.74 (2H, t, J=6.8 Hz), 3.94 (2H, t, J=5.6Hz), 4.24 (2H, t, J=6.7 Hz), 6.45 (1H, d, J=7.3 Hz), 6.60-6.74 (2H, m),7.02-7.18 (2H, m), 7.41-7.70 (6H, m), 7.88-8.00 (1H, m), 8.35 (1H, d,J=8.3 Hz).

EXAMPLE 39 Synthesis of1,3,3,5-tetramethyl-7-{3-[2-(1-oxo-1H-isoquinolin-2-yl)ethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.53 (3H, s), 1.89-2.04 (2H, m), 2.87 (2H, t, J=6.8 Hz),3.07 (2H, t, J=6.2 Hz), 3.38 (3H, s), 3.39 (3H, s), 4.03 (2H, t, J=6.1Hz), 4.08-4.21 (2H, m), 6.47 (1H, d, J=7.3 Hz), 6.70 (1H, d, J=2.7 Hz),6.75 (1H, dd, J=2.7 and 9.0 Hz), 7.09 (1H, d, J=8.9 Hz), 7.13 (1H, d,J=7.4 Hz), 7.41-7.55 (2H, m), 7.60-7.70 (1H, m), 8.41 (1H, d, J=8.0 Hz).

EXAMPLE 40 Synthesis of1,3,3,5-tetramethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.33 (3H, s), 2.09-2.38 (2H, m), 3.01-3.56 (6H, m), 3.30(3H, s), 3.32 (3H, s), 3.93-4.18 (2H, m), 4.30-4.54 (2H, m), 6.62-6.73(1H, m), 6.73-6.96 (2H, m), 7.34 (1H, d, J=8.9 Hz), 7.48-7.62 (2H, m),7.62-7.81 (2H, m), 8.12-8.38 (3H, m), 8.76-9.05 (2H, m).

EXAMPLE 41 Synthesis of tert-butylmethyl-(2-{(2-nitrobenzenesulfonyl)-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)carbamate

Using an appropriate starting material and following the procedure ofExample 21, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.46 (9H, s), 1.53 (3H, s), 2.01-2.15 (2H, m), 2.87 (3H,s), 3.39 (3H, s), 3.41 (3H, s), 3.43-3.48 (4H, m), 3.58 (2H, t, J=6.9Hz), 3.99 (2H, t, J=5.5 Hz), 6.69 (1H, d, J=2.7 Hz), 6.75 (1H, dd, J=2.7and 8.9 Hz), 7.12 (1H, d, J=9.1 Hz), 7.57-7.72 (3H, m), 7.98-8.08 (1H,m).

EXAMPLE 42 Synthesis of tert-butylmethyl-{2-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propylamino]ethyl}carbamate

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (3H, s), 1.46 (9H, s), 1.53 (3H, s), 1.91-2.04 (2H, m), 2.80 (2H,t, J=6.5 Hz), 2.84 (2H, t, J=7.0 Hz), 2.88 (3H, s), 3.35 (2H, t, J=6.5Hz), 3.39 (3H, s), 3.41 (3H, s), 4.06 (2H, t, J=6.2 Hz), 6.73 (1H, d,J=2.7 Hz), 6.81 (1H, dd, J=2.7 and 9.0 Hz), 7.13 (1H, d, J=9.0 Hz).

EXAMPLE 43 Synthesis of tert-butylmethyl-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)carbamate

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (3H, s), 1.44 (9H, br), 1.53 (3H, s), 1.90-2.02 (2H, m), 2.63 (2H,t, J=6.9 Hz), 2.67 (2H, t, J=6.9 Hz), 2.79 (3H, br), 3.33 (2H, br), 3.40(3H, s), 3.41 (3H, s), 3.65 (2H, s), 4.00 (2H, t, J=6.1 Hz), 6.66 (1H,d, J=2.7 Hz), 6.75 (1H, dd, J=2.7 and 8.9 Hz), 7.13 (1H, d, J=8.9 Hz),7.25 (2H, d, J=6.5 Hz), 8.48 (2H, d, J=5.7 Hz).

EXAMPLE 44 Synthesis of1,3,3,5-tetramethyl-7-{3-[(2-methylaminoethyl)-pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

A 4N-hydrogen chloride ethyl acetate solution (3.2 ml) was added to anethyl acetate solution (30 ml) of tert-butylmethyl-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)carbamate(1.43 g, 2.5 mmol) and stirred at room temperature overnight. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in dichloromethane, and trifluoroacetic acid (3 ml) wasadded thereto. Stirring was conducted at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure, and theresidue was dissolved in a dichloromethane-methanol mixture solvent.Polymer-bonded quaternary ammonium carbonate (PL-HcO3MP) was addedthereto to neutralize the mixture. The resulting reaction mixture wasfiltered. The filtrate was concentrated under reduced pressure tothereby obtain 1.44 g (yield: quantitative) of1,3,3,5-tetramethyl-7-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a pale brown oil.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, s), 1.53 (3H, s), 1.92-2.06 (2H, m), 2.56 (3H, s), 2.72 (2H,t, J=7.0 Hz), 2.89 (2H, t, J=5.6 Hz), 3.03 (2H, t, J=5.6 Hz), 3.38 (3H,s), 3.39 (3H, s), 3.68 (2H, s), 4.00 (2H, t, J=5.6 Hz), 6.67 (1H, d,J=2.7 Hz), 6.75 (1H, dd, J=2.7 and 8.9 Hz), 7.12 (1H, d, J=8.9 Hz), 7.30(2H, d, J=5.8 Hz), 8.51 (2H, d, J=4.6 Hz).

EXAMPLE 45 Synthesis ofN-methyl-N-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)benzamidedihydrochloride

1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (WSC) (144mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (115 mg, 0.75 mmol)were added to a DMF solution (5 ml) of1,3,3,5-tetramethyl-7-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (227 mg, 0.5mmol) and benzoic acid (92 mg, 0.75 mmol), and stirred at roomtemperature overnight. Water was added to the reaction mixture, andextraction with ethyl acetate was performed. The organic layer waswashed with water, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate:methanol=1:0→10:1). The purified productwas concentrated under reduced pressure, and a 4N-hydrogen chlorideethyl acetate solution (0.14 ml) was added to the residue (an ethylacetate solution). The precipitated insoluble matter was collected byfiltration, washed with ethyl acetate, and dried to thereby obtain 120.5mg (yield: 40%) ofN-methyl-N-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)benzamidedihydrochloride as a white powder.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.34 (3H, s), 2.08-2.31 (2H, m), 2.94 (3H, s), 2.99-3.38(4H, m), 3.29 (3H, s), 3.32 (3H, s), 3.66-3.89 (2H, m), 4.00-4.15 (2H,m), 4.29-4.55 (2H, m), 6.80-6.89 (2H, m), 7.32 (1H, d, J=8.7 Hz), 7.41(5H, br-s), 8.02 (2H, br-s), 7.58-8.78 (2H, m).

EXAMPLE 46 Synthesis of 2,3-dihydrobenzofuran-7-carboxylic acidmethyl-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)amidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 45, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.77 (3H, s), 1.34 (3H, s), 2.08-2.34 (2H, m), 2.76-3.33 (8H, m), 3.29(3H, s), 3.32 (3H, s), 3.69-3.92 (2H, m), 3.95-4.18 (3H, m), 4.39-4.63(4H, m), 6.72-6.92 (3H, m), 6.92-7.10 (1H, m), 7.19-7.37 (2H, m),7.80-8.18 (2H, m), 8.79 (2H, br-s).

EXAMPLE 47 Synthesis of2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide

Potassium carbonate (1.89 g, 13.7 mmol) was added to a DMF solution (50ml) of 2-nitro-N-(2-pyridin-3-ylethyl)benzene sulfonamide (1.40 g, 4.56mmol) and1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(2.16 g, 5.0 mmol), and stirred at room temperature overnight. Water wasadded to the reaction mixture, and extraction with ethyl acetate wasperformed. The organic layer was washed with water and a saturatedsodium chloride aqueous solution in this order, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate:methanol=1:0→10:1). The purified product was concentrated underreduced pressure to thereby obtain 2.99 g (yield: quantitative) of2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamideas a yellow oil.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.15 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.04-2.12 (2H, m),2.88-2.96 (2H, m), 3.40 (3H, s), 3.55-3.62 (4H, m), 3.64-3.76 (1H, m),4.01 (2H, t, J=5.9 Hz), 4.08-4.23 (1H, m), 6.70 (1H, d, J=2.7 Hz), 6.78(1H, dd, J=9.0 and 2.0 Hz), 7.17-7.22 (2H, m), 7.53 (1H, dt, J=7.9 and2.1 Hz), 7.59-7.70 (2H, m), 7.99-8.02 (2H, m), 8.42 (1H, d, J=1.7 Hz),8.46 (1H, dd, J=4.8 and 1.7 Hz).

EXAMPLE 48 Synthesis of1-ethyl-7-{3-[(1H-imidazol-2-ylmethyl)-(2-pyridin-3-ylethyl)amino]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, s), 1.15 (3H, t, J=7.0 Hz), 1.52 (3H, s), 1.91-1.99 (2H, m),2.68-2.90 (6H, m), 3.39 (3H, s), 3.60-3.78 (1H, m), 3.78-4.02 (4H, m),4.07-4.22 (1H, m), 6.67 (1H, d, J=2.5 Hz), 6.76 (1H, dd, J=2.5 and 9.0Hz), 6.85-6.94 (2H, m), 7.12-7.28 (2H, m), 7.46 (1H, d, J=7.8 Hz), 8.44(1H, d, J=4.5 Hz), 8.47 (1H, s).

EXAMPLE 49 Synthesis of1-ethyl-7-{3-[(3H-imidazol-4-ylmethyl)-(2-pyridin-3-ylethyl)amino]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.01 (3H, t, J=6.9 Hz), 1.32 (3H, s), 2.18-2.38 (2H, m),3.17-3.42 (6H, m), 3.33 (3H, s), 3.58-3.72 (1H, m), 4.00-4.19 (3H, m),4.40-4.52 (2H, m), 6.88-6.98 (2H, m), 7.42 (1H, d, J=8.8 Hz), 7.73 (1H,dd, J=5.3 and 7.5 Hz), 7.87 (1H, s), 8.21 (1H, d, J=7.5 Hz), 8.67 (1H,d, J=5.3 Hz), 8.78 (1H, s), 8.91 (1H, s).

EXAMPLE 50 Synthesis of1,3,3,5-tetramethyl-7-{3-[(2-methylbenzyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.33 (3H, s), 2.20-2.42 (2H, m), 2.50 (3H, s), 3.08-3.40(2H, m), 3.30 (3H, s), 3.33 (3H, s), 3.49-3.62 (4H, m), 4.08-4.21 (2H,m), 4.37-4.61 (2H, m), 6.82-6.96 (2H, m), 7.17-7.41 (4H, m), 7.78 (1H,d, J=7.3 Hz), 7.99 (1H, dd, J=5.7 and 7.6 Hz), 8.49 (1H, d, J=8.0 Hz),8.82 (1H, d, J=5.3 Hz), 8.94 (1H, s).

EXAMPLE 51 Synthesis of1,3,3,5-tetramethyl-7-{3-[(2-pyridin-3-ylethyl)-(quinolin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.74 (3H, s), 1.32 (3H, s), 2.13-2.45 (2H, m), 3.14-3.78 (6H, m), 3.29(3H, s), 3.31 (3H, s), 3.98-4.17 (4H, m), 6.73-6.89 (2H, m), 7.33 (1H,d, J=8.8 Hz), 7.90 (1H, t, J=7.7 Hz), 7.98-8.12 (2H, m), 8.37 (1H, d,J=8.4 Hz), 8.53 (1H, d, J=8.2 Hz), 8.38-8.69 (2H, m), 8.83 (1H, d, J=5.6Hz), 8.95 (1H, s), 9.22 (1H, d, J=4.9 Hz).

EXAMPLE 52 Synthesis of 1,3,3,5-tetramethyl-7-{3-[(2-methylpyridin-4-ylmethyl)(2-pyridin-3-ylethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.33 (3H, s), 2.10-2.37(2H, m), 2.69 (3H, s), 3.00-3.98(6H, m), 3.30 (3H, s), 3.33 (3H, s), 3.98-4.22 (2H, m), 4.41-4.78 (2H,m), 6.82-6.95 (3H, m), 7.37 (1H, d, J=8.6 Hz), 7.88-8.26 (3H, m),8.68-8.82 (2H, m), 8.85 (1H, s).

EXAMPLE 53 Synthesis of7-{3-[(3,5-dichloropyridin-4-ylmethyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.02 (3H, t, J=7.0 Hz), 1.33 (3H, s), 2.09-2.44 (2H, m),2.98-3.60 (6H, m), 3.33 (3H, s), 3.60-3.77 (1H, m), 3.98-4.18 (3H, m),4.20-4.62 (2H, m), 6.80-7.00 (2H, m), 7.41 (1H, d, J=8.7 Hz), 7.97-8.10(1H, m), 8.49-8.78 (3H, m), 8.84 (1H, d, J=5.4 Hz), 8.96 (1H, s).

EXAMPLE 54 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(3-methylpyridin-4-ylmethyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=6.9 Hz), 1.32 (3H, s), 2.11-2.42 (2H, m),2.56 (3H, s), 3.08-3.59 (8H, m), 3.59-3.77 (1H, m), 3.95-4.18 (2H, m),4.41-4.90 (4H, m), 6.82-6.97 (2H, m), 7.41 (1H, d, J=8.8 Hz), 8.03 (1H,dd, J=5.7 and 7.8 Hz), 8.30-8.69 (1H, m), 8.56 (1H, d, J=8.1 Hz),8.72-8.88 (3H, m), 8.96 (1H, s).

EXAMPLE 55 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-3-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 1.01 (3H, t, J=6.9 Hz), 1.32 (3H, s), 2.27-2.41 (2H, m),3.20-3.36 (2H, m), 3.33 (3H, s), 3.38-3.57 (4H, m), 3.67-3.76 (1H, m),4.00-4.18 (3H, m), 4.52-4.75 (2H, m), 6.87-6.97 (2H, m), 7.42 (1H, d,J=8.8 Hz), 7.83 (1H, dd, J=5.3 and 7.9 Hz), 7.99 (1H, dd, J=5.7 and 8.0Hz), 8.51 (1H, d, J=8.1 Hz), 8.65 (1H, d, J=7.9 Hz), 8.78-8.87 (2H, m),8.95 (1H, s), 9.13 (1H, s).

EXAMPLE 56 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.19-2.40 (2H, m),3.20-3.57 (4H,m), 3.32 (3H, s), 3.61-3.72 (1H, m), 3.99-4.10 (3H, m),4.35-4.85 (4H, m), 6.70 (1H, d, J=7.4 Hz), 6.81-6.97 (2H, m), 7.39 (1H,d, J=9.0 Hz), 7.50-7.57 (2H, m), 7.66-7.92 (3H, m), 8.22 (1H, d, J=8.0Hz), 8.50-8.71 (1H, m), 8.78-8.90 (1H, m), 9.02-9.18 (1H, m).

EXAMPLE 57 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]thiazol-2-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.88-2.00 (m, 2H),2.82 (t, J=6.3 Hz, 2H), 3.01 (t, J=6.3 Hz, 2H), 3.36 (s, 3H), 3.61-3.74(m, 1H), 3.88 (t, J=6.1 Hz, 2H), 4.07 (s, 2H), 4.08-4.23 (m, 3H), 6.42(d, J=7.3 Hz, 1H), 6.60-6.68 (m, 2H), 7.06 (d, J=7.3 Hz, 1H), 7.12-7.15(m, 2H), 7.48-7.49 (m, 2H), 7.64 (d, J=7.4 Hz, 1H), 7.67 (d, J=3.3 Hz,1H), 8.39 (d, J=7.4 Hz, 1H).

EXAMPLE 58 Synthesis of1-ethyl-7-(3-{(3-fluorobenzyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (s, 3H), 1.15 (t, J=7.0 Hz, 3H), 1.53 (s, 3H), 1.80-1.96 (m, 2H),2.70 (t, J=6.4 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 3.35 (s, 3H), 3.67 (s,2H), 3.66-3.76 (m, 1H), 3.83 (t, J=6.0 Hz, 2H), 4.08 (t, J=6.0 Hz, 2H),4.00-4.21 (m, 1H), 6.40 (d, J=7.4 Hz, 1H), 6.55-6.61 (m, 2H), 6.80-6.95(m, 1H), 6.88-7.00 (m, 3H), 7.05-7.18 (m, 2H), 8.41-8.50 (m, 2H), 7.64(t, J=8.0 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H).

EXAMPLE 59 Synthesis of1-ethyl-7-(3-{(3-methoxybenzyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.80-1.96 (m, 2H),2.70 (t, J=6.8 Hz, 2H), 2.90 (t, J=6.2 Hz, 2H), 3.36 (s, 3H), 3.65 (s,2H), 3.68 (s, 3H), 3.65-3.72 (m, 1H), 3.84 (t, J=6.2 Hz, 2H), 4.06 (t,J=6.2 Hz, 2H), 4.10-4.20 (m, 1H), 6.38 (d, J=7.3 Hz, 1H), 6.55-6.60 (m,2H), 6.67-6.73 (m, 1H), 6.79-6.81 (m, 2H), 6.95-7.30 (m, 3H), 7.39-7.50(m, 2H), 7.60-7.67 (m, 1H), 8.40 (d, J=1.2 Hz, 1H).

EXAMPLE 60 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]thiophen-2-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.80-1.96 (m, 2H),2.69 (t, J=6.8 Hz, 2H), 2.91 (t, J=6.2 Hz, 2H), 3.35 (s, 3H), 3.65-3.78(m, 1H), 3.82 (t, J=6.2 Hz, 2H), 3.89 (s, 2H), 4.07 (t, J=6.2 Hz, 2H),4.10-4.25 (m, 1H), 6.40 (d, J=7.3 Hz, 1H), 6.38-6.49 (m, 2H), 6.87-6.89(m, 2H), 7.02-7.28 (m, 3H), 7.42-7.50 (m, 2H), 7.60-7.64 (m, 1H), 8.40(d, J=1.2 Hz, 1H).

EXAMPLE 61 Synthesis of7-(3-{bis-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

(1-Oxo-1H-isoquinolin-2-yl)acetaldehyde (207 mg, 1.1 mmol) was added toa 1,2-dichloroethane solution (4 ml) of7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (329 mg, 1.0 mmol) and sodiumtriacetoxyhydroborate (381 mg, 1.8 mmol), and stirred at roomtemperature overnight. Water was added to the reaction mixture, andextraction with ethyl acetate was performed. The organic layer waswashed with water, and a saturated sodium chloride aqueous solution, inthis order, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (dichloromethane:methanol=20:1). The purified product wasconcentrated under reduced pressure to thereby obtain7-(3-{bis-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.74-1.82 (m, 2H),2.75 (t, J=7.3 Hz, 2H), 2.94 (t, J=6.2 Hz, 4H), 3.34 (s, 3H), 3.62-3.75(m, 3H), 4.02 (t, J=6.2 Hz, 4H), 4.12-4.23 (m, 1H), 6.16 (d, J=7.3 Hz,2H), 6.50 (dd, J=8.9 and 2.7 Hz, 1H), 6.56 (d, J=2.7 Hz, 1H), 6.91 (d,J=7.3 Hz, 2H), 7.09 (d, J=8.9 Hz, 1H), 7.39-7.62 (m, 4H), 7.59-7.68 (m,2H), 8.41 (d, J=7.9 Hz, 2H).

EXAMPLE 62 Synthesis of1-ethyl-7-(3-{[2-(7-methoxy-2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.51 (s, 3H), 1.90-2.00 (m, 4H),2.58 (t, J=6.8 Hz, 2H), 2.68 (t, J=6.8 Hz, 2H), 3.38 (s, 3H), 3.61 (s,2H), 3.62-3.72 (m, 1H), 3.95-4.00 (m, 4H), 4.08-4.22 (m, 1H), 6.44 (d,J=7.3 Hz, 1H), 6.68 (d, J=2.7 Hz, 1H), 6.75 (dd, J=9.0 and 2.7 Hz, 1H),6.95 (d, J=7.3 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.25-7.27 (m, 2H),7.45-7.52 (m, 2H), 7.60-7.70 (m, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.48 (d,J=1.5 Hz, 2H).

EXAMPLE 63 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (s, 3H), 1.17 (t, J=7.0 Hz, 3H), 1.54 (s, 3H), 1.92-2.04 (m, 2H),2.80-2.86 (m, 4H), 3.41 (s, 3H), 3.76 (s, 2H), 3.68-3.78 (m, 1H), 4.01(t, J=6.0 Hz, 2H), 4.10-4.22 (m, 1H), 4.44 (t, J=7.0 Hz, 2H), 6.66-6.70(m, 2H), 6.76 (dd, J=8.9 and 2.9 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H),7.07-7.11 (m, 4H), 7.38-7.46 (m, 1H), 7.57 (d, J=6.5 Hz, 1H), 7.68 (d,J=9.5 Hz, 1H), 8.44 (d, J=5.9 Hz, 2H).

EXAMPLE 64 Synthesis of1-ethyl-7-{3-[(2-(6-methoxy-2-oxo-2H-quinolin-1-yl)ethyl)pyridin-4-ylmethylamino]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.89-2.00 (m, 2H),2.81 (m, 4H), 3.39 (s, 3H), 3.74 (s, 2H), 3.65-3.77 (m, 1H), 3.85 (s,3H), 3.99 (t, J=6.0 Hz, 2H), 4.11-4.28 (m, 1H), 4.40 (t, J=6.9 Hz, 2H),6.64-6.70 (m, 2H), 6.74 (dd, J=8.9 and 2. 9 Hz, 1H), 6.96-7.04 (m, 3H),7.16-7.20 (m, 3H), 7.60 (d, J=9.5 Hz, 1H), 8.43 (d, J=5.9 Hz, 2H).

EXAMPLE 65 Synthesis of1-ethyl-7-(3-{[2-(6-methoxyquinolin-2-yloxy)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.82 (s, 3H), 1.12 (t, J=7.1 Hz, 3H), 1.51 (s, 3H), 1.90-2.05 (m, 2H),2.77 (t, J=7.0 Hz, 2H), 2.97 (t, J=7.0 Hz, 2H), 3.34 (s, 3H), 4.58-5.59(m, 1H), 3.77 (s, 2H), 3.90 (s, 3H), 3.95-4.04 (m, 2H), 4.04-4.19 (m,1H), 4.50-4.63 (m, 2H), 6.59-6.66 (m, 2H), 6.83 (d, J=8.8 Hz, 1H), 7.04(d, J=2.8 Hz, 1H), 7.11 (d, J=8.9 Hz, 1H), 7.24-7.27 (m, 3H), 7.67 (d,J=9.1 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.42 (d, J=5.9 Hz, 2H).

EXAMPLE 66 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.89-1.97 (m, 2H),2.53-2.64 (m, 2H), 2.68-2.77 (m, 4H), 2.86 (t, J=8.0 Hz, 2H), 3.38 (s,3H), 3.69 (s, 2H), 3.60-3.78 (m, 1H), 3.93-4.20 (m, 5H), 6.67 (d, J=2.7Hz, 1H), 6.72-6.84 (m, 2H), 6.79 (t, J=8.2 Hz, 1H), 7.10-7.22 (m, 5H),8.44 (d, J=6.0 Hz, 2H).

EXAMPLE 67 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.88 (s, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.54 (s, 3H), 1.89-1.97 (m, 2H),2.74 (t, J=6.8 Hz, 2H), 2.83-2.95 (m, 2H), 3.39 (s, 3H), 3.69 (s, 2H),3.68-3.74 (m, 1H), 3.89 (t, J=6.0 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H),4.11-4.21 (m, 1H), 6.53-6.70 (m, 3H), 7.05 (d, J=7.2 Hz, 1H), 7.10 (d,J=5.9 Hz, 2H), 7.20 (d, J=8.9 Hz, 1H), 7.32 (d, J=5.3 Hz, 1H), 7.63 (d,J=5.3 Hz, 1H), 8.32 (d, J=5.9 Hz, 2H).

EXAMPLE 68 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.88 (s, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.54 (s, 3H), 1.89-1.97 (m, 2H),2.74 (t, J=6.8 Hz, 2H), 2.83-2.95 (m, 2H), 3.39 (s, 3H), 3.68 (s, 2H),3.68-3.74 (m, 1H), 3.90 (t, J=6.0 Hz, 2H), 4.05-4.21 (m, 3H), 6.56 (d,J=7.1 Hz, 1H), 6.60-6.70 (m, 2H), 7.03-7.10 (m, 3H), 7.16-7.23 (m, 2H),7.73 (d, J=5.2 Hz, 1H), 8.31 (d, J=5.9 Hz, 2H).

EXAMPLE 69 Synthesis of1-ethyl-7-(3-{[2-(8-methoxy-2-oxo-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (s, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.54 (s, 3H), 1.89-1.97 (m, 2H),2.78 (t, J=6.7 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H), 3.41 (s, 3H), 3.75 (s,3H), 3.68-3.79 (m, 3H), 3.98 (t, J=6.2 Hz, 2H), 4.05-4.21 (m, 1H), 4.80(t, J=7.7 Hz, 2H), 6.65-6.78 (m, 3H), 6.96-7.03 (m, 1H), 7.11-7.23 (m,5H), 7.62 (d, J=9.4 Hz, 1H), 8.41 (d, J=6.0 Hz, 2H).

EXAMPLE 70 Synthesis of1-ethyl-7-(3-{[2-(8-methoxyquinolin-2-yloxy)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.83 (s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.51 (s, 3H), 1.89-2.03 (m, 2H),2.76 (t, J=6.7 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H), 3.35 (s, 3H), 3.59-3.67(m, 1H), 3.80 (s, 2H), 3.99 (s, 3H), 3.95-4.07 (m, 2H), 4.10-4.19 (m,1H), 4.70 (t, J=7.0 Hz, 2H), 6.58-6.70 (m, 2H), 6.89 (d, J=8.8 Hz, 1H),6.95-7.05 (m, 1H), 7.11 (d, J=8.9 Hz, 1H), 7.23-7.38 (m, 4H), 7.97 (d,J=8.8 Hz, 1H), 8.41 (d, J=6.0 Hz, 2H).

EXAMPLE 71 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (s, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.82-1.95 (m, 2H),2.72 (t, J=6.8 Hz, 2H), 2.76-2.89 (m, 2H), 3.38 (s, 3H), 3.68 (s, 2H),3.63-3.78 (m, 1H), 3.87 (t, J=6.0 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H),4.11-4.20 (m, 1H), 6.43 (d, J=7.4 Hz, 1H), 6.60 (d, J=2.8 Hz, 1H), 6.67(dd, J=9.0 and 2.8 Hz, 1H), 6.96 (d, J=2.9 Hz, 1H), 7.05-7.11 (m, 3H),7.19 (d, J=9.0 Hz, 1H), 7.50 (d, J=2.9 Hz, 1H), 8.35 (d, J=6.0 Hz, 2H).

EXAMPLE 72 Synthesis of1-ethyl-7-(3-{[2-(6-methoxy-2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (s, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.86-1.96 (m, 2H),1.87-2.01 (m, 2H), 2.55-2.61 (m, 2H), 2.70-2.85 (m, 6H), 3.40 (s, 3H),3.62-3.78 (m, 1H), 3.71 (s, 2H), 3.75 (s, 3H), 3.98-4.21 (m, 3H), 6.48(d, J=2.3 Hz, 1H), 6.49 (dd, J=8.2 and 2.3 Hz, 1H), 6.69 (d, J=2.7 Hz,1H), 6.76 (dd, J=8.0 and 2.7 Hz , 1H), 7.06 (d, J=8.2 Hz, 1H), 7.18-7.23(m, 3H), 8.44 (d, J=6.0 Hz, 2H).

EXAMPLE 73 Synthesis of1-ethyl-7-(3-{[2-(7-methoxy-2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-tri-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.84-1.96 (m, 2H),2.55-2.63 (m, 2H), 2.62-2.71 (m, 4H), 2.75-2.84 (m, 2H), 3.38 (s, 3H),3.68 (s, 2H), 3.77 (s, 3H), 3.64-3.76 (m, 1H), 3.96-4.23 (m, 5H),6.61-6.75 (m, 5H), 7.16-7.22 (m, 3H), 8.45 (d, J=6.0 Hz, 2H).

EXAMPLE 74 Synthesis ofN-(3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl)-N-(2-(7-methyl-1-oxo-1H-isoquinolin-2-yl)ethyl)-2-nitrobenzenesulfonamide

N,N,N′,N′-Tetra methyl azodicarboxamide (TMAD) (118 mg) and tri-n-butylphosphine (0.17 ml) were added to a THF solution (5 ml) ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-nitrobenzenesulfonamide(231 mg) and 2-(2-hydroxyethyl)-7-methyl-2H-isoquinolin-1-one (93 mg),and stirred at room temperature overnight. Water was added to thereaction mixture, and extraction with dichloromethane was performed. Theorganic layer was dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate:methanol=20:1→10:1). The purified productwas concentrated to dryness under reduced pressure to thereby obtain 205mg (yield: 65%) ofN-(3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl)-N-(2-(7-methyl-1-oxo-1H-isoquinolin-2-yl)ethyl)-2-nitrobenzenesulfonamideas a white amorphous solid.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.04-2.19 (2H, m),2.49 (3H, s), 3.39 (3H, s), 3.62 (2H, t, J=6.7 Hz), 3.60-3.78 (1H, m),3.73 (2H, t, J=6.7 Hz), 3.94 (2H, t, J=5.7 Hz), 4.10-4.26 (1H, m), 4.23(2H, t, J=6.7 Hz), 6.43 (1H, d, J=7.3 Hz), 6.68 (1H, d, J=2.7 Hz), 6.72(1H, dd, J=2.7 and 8.9 Hz), 7.08 (1H, d, J=7.3 Hz), 7.17 (1H, d, J=8.9Hz), 7.39 (1H, d, J=8.1 Hz), 7.46-7.54 (1H, m), 7.54-7.62 (3H, m),7.93-8.03 (1H, m), 8.16 (1H, s).

EXAMPLE 75 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[2-(7-methyl-1-oxo-1H-isoquinolin-2-yl)ethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.14 (3H, t, J=7.0 Hz), 1.52 (3H, s), 1.89-2.05 (2H, m),2.48 (3H, s), 2.87 (2H, t, J=6.7 Hz), 3.06 (2H, t, J=6.2 Hz), 3.38 (3H,s), 3.61-3.76 (1H, m), 4.02 (2H, t, J=6.1 Hz), 4.14 (2H, t, J=6.2 Hz),4.10-4.22 (1H, m), 6.44 (1H, d, J=7.3 Hz), 6.69 (1H, d, J=2.7 Hz), 6.75(1H, dd, J=2.7 and 8.9 Hz), 7.06 (1H, d, J=7.3 Hz), 7.15 (1H, d, J=8.9Hz), 7.40 (1H, d, J=8.0 Hz), 7.45-7.50 (1H, m), 8.22 (1H, s).

EXAMPLE 76 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-methyl-1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using appropriate starting materials and following the procedures ofExamples 7 and 6, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:0.74 (3H, s), 1.01 (3H, t, J=6.9 Hz), 1.32 (3H,s), 2.00-2.24 (2H, m), 2.44 (3H, s), 2.89-4.60 (10H, m), 3.30 (3H, s),4.81 (2H, s), 6.62 (1H, d, J=7.1 Hz), 6.78 (1H, d, J=9.1 Hz), 6.85 (1H,s), 7.36 (1H, d, J=9. 1 Hz), 7.45 (1H, d, J=7.1 Hz), 7.95-8.13 (5H, m),8.86 (2H, d, J=6.0 Hz).

EXAMPLE 77 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

4-Pyridinecarbaldehyde (0.64 ml, 6.8 mmol) was added to a methanolsolution (10 ml) of7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(2.18 g, 6.8 mmol), and stirred under a nitrogen atmosphere at roomtemperature for 1.5 hours. The reaction mixture was cooled in an icewater bath, and sodium borohydride (257 mg, 6.8 mmol) was added theretoat 0° C. The mixture was then stirred at room temperature overnight.Water was added to the reaction mixture, and extraction with ethylacetate was performed. The organic layer was washed with water and asaturated sodium chloride aqueous solution, in this order, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate:methanol=9:1→3:2). The purified product was concentrated underreduced pressure to thereby obtain 2.35 g (yield: 84%) of1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dioneas a pale yellow oil.

¹H-NMR (CDCl₃) δppm:

0.86 (s, 3H), 1.12 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.97-2.09 (m, 2H),2.84 (t, J=6.8 Hz, 2H), 3.39 (s, 3H), 3.62-3.78 (m, 1H), 3.85 (s, 2H),4.09 (t, J=6.1 Hz, 2H), 4.06-4.24 (m, 1H), 6.71 (d, J=2.8 Hz, 1H), 6.80(dd, J=9.0 and 2.8 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.26-7.27 (m, 2H),8.53 (d, J=6.0 Hz, 2H).

EXAMPLES 78 to 456

Using appropriate starting materials and following the procedures of theabove-mentioned Examples, the compounds shown in Tables 1 to 33 wereprepared.

TABLE 1

Example R101 R102 R103 R104 R105 MS(M + 1) 78 —H —H —H —H —H 581 79 —H—H —CO₂H —H —H 625 80 —H —H —C₆H₅ —H —H 657 81 —H —H —OCH₃ —H —H 611 82—H —H —OH —H —H 597 83 —H —H —CH₃ —H —H 595 84 —H —H —CH(CH₃)₂ —H —H 62385 —H —H —CN —H —H 606 86 —H —H —OC₂H₅ —H —H 625 87 —H —OH —H —H —H 59788 —H —H —NHCOCH₃ —H —H 638 89 —Cl —H —H —H —H 615 90 —H —Cl —H —H —H615 91 —H —H —Cl —H —H 615 92 —F —H —H —H —H 599 93 —CN —H —H —H —H 60694 —CF₃ —H —H —H —H 649 95 —H —CF₃ —H —H —H 649 96 —H —CH₃ —H —H —H 59597 —H —H —CF₃ —H —H 649 98 —H —H —C₂H₅ —H —H 609 99 —H —H —F —H —H 599100 —CH₃ —H —H —H —H 595 101 —H —CN —H —H —H 606 102 —OCH₃ —H —H —H —H611 103 —H —H —SCH₃ —H —H 627 104 —H —H —OCH(CH₃)₂ —H —H 639

TABLE 2

Example R101 R102 R103 R104 R105 MS(M + 1) 105 —H —C₆H₅ —H —H —H 657 106—H —H -2-THIENYL —H —H 663 107 —OH —H —H —H —H 597 108 —H —H -3-PYRIDYL—H —H 658 109 —H -3-PYRIDYL —H —H —H 658 110 -3-PYRIDYL —H —H —H —H 658111 -2-THIENYL —H —H —H —H 663 112 —H —H -2-FURYL —H —H 647

TABLE 3

Example R101 R102 R103 R104 R105 MS(M + 1) 113 —H —H

—H —H 648 114 —H —H

—H —H 647 115 —H —H

—H —H 664 116

—H —H —H —H 679 117 —H

—H —H —H 647 118 —H —H

—H —H 680 119 —H —H

—H —H 661 120 —H

—H —H —H 661 121 —H —H

—H —H 659 122 —H

—H —H —H 659

TABLE 4

Example R106 MS(M + 1) 123 -2-IMIDAZOLYL 571 124 -2-PYRIDYL 582 125-3-THIENYL 587 126 -3-INDOLYL 620 127 -2-BENZOFURANYL 621 128-4-QUINOLYL 632 129 -2-QUINOLYL 632 130 —CH═CHC₆H₅(trans) 607 131-4-IMIDAZOLYL 571 132 -2-FURYL 571 133 -2-NAPHTHYL 631 134-5-BENZOFURANYL 621 135 -3-QUINOLYL 632 136 —CH₂C₆H₅ 595 137 -8-QUINOLYL632 138 —CH(CH₃)C₆H₅ 609 139 —(CH₂)₂C₆H₅ 609

TABLE 5

Example R106 MS(M + 1) 140

585 141

601 142

647 143

634 144

621 145

627 146

664 147

597 148

615 149

631

TABLE 6

Example R106 MS(M + 1) 150

651 151

599 152

651 153

621 154

599 155

585 156

662 157

635 158

615

TABLE 7

Example R106 MS(M + 1) 159

585 160

625 161

637 162

625 163

620 164

665 165

623 166

639 167

655

TABLE 8

Example R106 MS(M + 1) 168

661 169

661 170

632 171

632 172

599 173

619 174

585 175

623

TABLE 9

Example R106 MS(M + 1) 176

621 177

621 178

654 179

637 180

637 181

596 182

601 183

635 184

600

TABLE 10

Example R106 MS(M + 1) 185

664 186

602 187

639 188

648 189

639 190

660 191

616 192

635 193

634 194

661

TABLE 11

Example R106 MS(M + 1) 195

622 196

638 197

636 198

585 199

615

TABLE 12

Example R101 R102 R103 R104 R105 MS(M + 1) 200 —H —H —H —H —H 515 201 —H—H —CO₂H —H —H 559 202 —H —H —C₆H₅ —H —H 591 203 —H —H —OCH₃ —H —H 545204 —H —H —H —OCH₃ —H 545 205 —H —H —OH —H —H 531 206 —H —H —CH₃ —H —H529 207 —H —H —CH(CH₃)₂ —H —H 557 208 —H —H —CN —H —H 540 209 —H —H—OC₂H₅ —H —H 559 210 —H —H —H —OH —H 531 211 —H —H —OH —OH —H 547 212 —H—H —H —H —CO₂H 559 213 —H —H —NHCOCH₃ —H —H 572 214 —H —H—O(CH₂)₃N(CH₃)₂ —H —H 616 215 —H —H —H —H —Cl 549 216 —H —H —H —Cl —H549 217 —H —H —Cl —H —H 549 218 —H —H —H —H —F 533 219 —H —H —H —H —CN540 220 —H —H —H —H —CF₃ 583 221 —H —H —H —CF₃ —H 583 222 —H —H —H —CH₃—H 529 223 —H —H —CF₃ —H —H 583 224 —H —H —C₂H₅ —H —H 543 225 —H —H —F—H —H 533 226 —H —H —H —H —CH₃ 529 227 —H —H —CO₂CH₃ —H —H 573

TABLE 13

Example R101 R102 R103 R104 R105 MS(M + 1) 228 —H —H —H —F —H 533 229 —H—H —H —CN —H 540 230 —H —H —H —H —OCH₃ 545 231 —H —H —SCH₃ —H —H 561 232—H —H —H —H —CO₂CH₃ 573 233 —H —H —SO₂CH₃ —H —H 593 234 —H —H —OCH(CH₃)₂—H —H 573 235 —H —H —H —C₆H₅ —H 591 236 —H —H —H —H —NHSO₂CH₃ 608 237 —H—H -1-IMIDAZOLYL —H —H 581 238 —H —H -2-THIENYL —H —H 597 239 —H —H —H—H —OH 531 240 —H —H -3-PYRIDYL —H —H 592 241 —H —H —H -3-PYRIDYL —H 592242 —H —H —H —H -3-PYRIDYL 592 243 —H —H —H —H -2-THIENYL 597 244 —H —H-2-FURYL —H —H 581

TABLE 14

Example R101 R102 R103 R104 R105 MS(M + 1) 245 —H —H

—H —H 582 246 —H —H —H —H

613 247 —H —H —H

—H 581 248 —H —H

—H —H 614 249 —H —H

—H —H 595 250 —H —H —H

—H 595 251 —H —H

—H —H 593 252 —H —H —H

—H 593 253 —H —H

—H —H 598

TABLE 15

Example R106 MS(M + 1) 254 -3-FURYL 505 255 -2-PYRIDYL 516 256-2-THIENYL 521 257 -3-THIENYL 521 258 -2-BENZOFURANYL 555 259-4-QUINOLYL 566 260 -2-QUINOLYL 566 261 —CH═CHC₆H₅(trans) 541 262-2-THIAZOLYL 522 263 -1-NAPHTHYL 565 264 -2-FURYL 505 265 -2-NAPHTHYL565 266 -5-BENZOFURANYL 555 267 -3-QUINOLYL 566 268 —CH₂C₆H₅ 529 269-8-QUINOLYL 566 270 —CH(CH₃)C₆H₅ 543 271 —(CH₂)₂C₆H₅ 543 272 -6-QUINOLYL566 273 -2-BENZTHIAZOLYL 572

TABLE 16

Example R106 MS(M + 1) 274

519 275

535 276

581 277

568 278

555 279

561 280

598 281

531 282

549 283

565

TABLE 17

Example R106 MS(M + 1) 284

585 285

533 286

585 287

555 288

533 289

519 290

596 291

569 292

549

TABLE 18

Example R106 MS(M + 1) 293

519 294

559 295

573 296

571 297

559 298

554 299

599 300

557 301

584

TABLE 19

Example R106 MS(M + 1) 302

573 303

575 304

589 305

595 306

595 307

566 308

566 309

533

TABLE 20

Example R106 MS(M + 1) 310

553 311

519 312

557 313

555 314

555 315

588 316

571 317

571 318

530

TABLE 21

Example R106 MS(M + 1) 319

535 320

569 321

534 322

598 323

536 324

573 325

582 326

573 327

594 328

550

TABLE 22

Example R106 MS(M + 1) 329

569 330

568 331

595 332

595 333

556 334

572 335

570 336

519 337

549

TABLE 23

Example R106 MS(M + 1) 338

559 339

598 340

530 341

530 342

530 343

530 344

596 345

607 346

595

TABLE 24

Example R106 MS(M + 1) 347

596 348

588 349

581 350

534 351

598 352

572 353

596 354

595 355

612

TABLE 25

Example R106 MS(M + 1) 356

572 357

555 358

535 359

587 360

595 361

601 362

585 363

579 364

612

TABLE 26

Example R106 MS(M + 1) 365

585 366

587 367

519 368

555 369

530

TABLE 27

Example R1 R2 R3 R4 MS(M + 1) 370 —CH₃ —H —H —CH₃ 474 371 —H —H —H —H446

TABLE 28

Exam- MS ple R101 R102 R103 R104 R105 (M + 1) 372 —H —H —H —H —H 571 373—H —H —CO₂H —H —H 615 374 —H —H —C₆H₅ —H —H 647 375 —H —H —OCH₃ —H —H601 376 —H —H —H —OCH₃ —H 601 377 —H —H —OH —H —H 587 378 —H —H —CH₃ —H—H 585 379 —H —H —CH(CH₃)₂ —H —H 613 380 —H —H —CN —H —H 596 381 —H —H—OC₂H₅ —H —H 615 382 —H —H —H —OH —H 587 383 —H —H —OH —OH —H 603 384 —H—H —H —H —CO₂H 615 385 —H —H —NHCOCH₃ —H —H 628 386 —H —H—O(CH₂)₃N(CH₃)₂ —H —H 672 387 —H —H —H —H —Cl 605 388 —H —H —H —Cl —H605 389 —H —H —Cl —H —H 605 390 —H —H —H —H —F 589 391 —H —H —H —H —CN596 392 —H —H —H —H —CF₃ 639 393 —H —H —H —CF₃ —H 639 394 —H —H —H —CH₃—H 585 395 —H —H —CF₃ —H —H 639 396 —H —H —C₂H₅ —H —H 599 397 —H —H —F—H —H 589 398 —H —H —H —H —CH₃ 585 399 —H —H —CO₂CH₃ —H —H 629

TABLE 29

Example R101 R102 R103 R104 R105 MS(M + 1) 400 —H —H —H —F —H 589 401 —H—H —H —CN —H 596 402 —H —H —H —H —OCH₃ 601 403 —H —H —SCH₃ —H —H 617 404—H —H —H —H —CO₂CH₃ 629 405 —H —H —SO₂CH₃ —H —H 649 406 —H —H —OCH(CH₃)₂—H —H 629 407 —H —H —H —C₆H₅ —H 647 408 —H —H —H —H —NHSO₂CH₃ 664 409 —H—H -1-IMIDAZOLYL —H —H 637 410 —H —H -2-THIENYL —H —H 653 411 —H —H

—H —H 638 412 —H —H

—H —H 654

TABLE 30

Example R106 MS(M + 1) 413 -3-FURYL 561 414 -2-IMIDAZOLYL 561 415-2-PYRIDYL 572 416 -3-PYRIDYL 572 417 -2-THIENYL 577 418 -3-THIENYL 577419 -2-BENZOFURANYL 611 420 -4-QUINOLYL 622 421 -2-QUINOLYL 622 422—CH═CHC₆H₅(trans) 597 423 -2-THIAZOLYL 578 424 -4-IMIDAZOLYL 561 425-1-NAPHTHYL 621 426 -2-FURYL 561 427 -2-NAPHTHYL 621 428 -5-BENZOFURANYL611

TABLE 31

Example R106 MS(M + 1) 429

575 430

591 431

637 432

624 433

611 434

617 435

654 436

587 437

605 438

621

TABLE 32

MS Example R106 (M + 1) 439

641 440

589 441

641 442

611 443

589 444

575 445

652 446

625 447

605

TABLE 33

MS Example R106 (M + 1) 448

575 449

615 450

629 451

627 452

615 453

610 454

655 455

613 456

629

Using appropriate starting materials and following the procedures ofReference Examples 1 to 62, the following object compounds weresynthesized.

REFERENCE EXAMPLE 63 (1-Oxo-1H-isoquinolin-2-yl)acetaldehyde

¹H-NMR (CDCl₃) δppm:

4.78 (s, 2H), 6.59 (d, J=7.3 Hz, 1H), 7.00 (d, J=7.3 Hz, 1H), 7.52-7.59(m, 2H) , 7.68-7.73 (m, 1H), 8.44 (d, J=8.9 Hz, 1H), 9.76 (s, 1H).

REFERENCE EXAMPLE 64 (2-Oxo-2H-quinolin-1-yl)acetaldehyde

¹H-NMR (CDCl₃) δppm:

5.15 (s, 2H), 6.76 (d, J=9.5 Hz, 1H) , 7.05 (d, J=8.5 Hz, 1H), 7.24-7.29(m, 1H), 7.54-7.60 (m, 1H), 7.61 (dd, J=7.7 and 1.5 Hz, 1H), 7.77 (d,J=9.5 Hz, 1H), 9.70 (s, 1H).

REFERENCE EXAMPLE 656-(2,2-Dihydroxyethyl)-6H-thieno[2,3-c]pyridin-7-one

¹H-NMR (DMSO-d₆) δppm:

3.98 (d, J=5.3 Hz, 2H), 5.11-5.16 (m, 1H), 6.04 (d, J=6.4 Hz, 1H), 6.66(d, J=7.1 Hz, 2H), 7.27 (d, J=5.2 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.84(d, J=5.2H, 1H).

REFERENCE EXAMPLE 66 5-(2,2-Dihydroxyethyl)-5H-furo[3,2-c]pyridin-4-one

¹H-NMR (DMSO-d₆) δppm:

3.88 (d, J=5.4 Hz, 2H), 4.95-5.03 (m, 1H), 6.08 (d, J=6.4 Hz, 2H), 6.69(dd, J=7.4, 0.8 Hz, 1H), 6.94 (dd, J=2.1 and 0.8 Hz, 1H), 7.50 (d, J=7.4Hz, 1H), 7.86 (d, J=2.1 Hz, 1H).

REFERENCE EXAMPLE 675-(2,2-Dihydroxyethyl)-5H-thieno[3,2-c]pyridin-4-one

¹H-NMR (DMSO-d₆) δppm:

3.90 (d, J=6.3 Hz, 2H), 4.99-5.04 (m, 1H), 6.07 (d, J=6.3 Hz, 2H), 6.86(d, J=7.2 Hz, 1H), 7.41-7.49 (m, 2H), 7.57-7.64 (m, 1H).

REFERENCE EXAMPLE 682-Bromo-5-(2,2-dihydroxyethyl)-5H-furo[3,2-c]pyridin-4-one

¹H-NMR (DMSO-d₆) δppm:

3.86 (d, J=5.4 Hz, 2H), 4.95-5.03 (m, 1H), 6.07 (d, J=6.4 Hz, 2H), 6.69(dd, J=7.4 and 0.8 Hz, 1H), 7.08 (d, J=0.8 Hz, 1H), 7.51 (d, J=7.4 Hz,1H).

REFERENCE EXAMPLE 695-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one

¹H-NMR (DMSO-d₆) δppm:

2.36 (s, 3H), 3.86 (d, J=5.4 Hz, 2H), 4.94-4.98 (m, 1H), 6.04 (d, J=6.4Hz, 2H), 6.52 (s, 1H), 6.59 (d, J=7.4 Hz, 1H), 7.41 (d, J=7.4H, 1H).

REFERENCE EXAMPLE 705-(2,2-Dihydroxyethyl)-2-ethyl-5H-thieno[3,2-c]pyridin-4-one

¹H-NMR (DMSO-d₆) δppm:

1.73 (t, J=7.5z, 3H), 3.31 (q, J=7.5 Hz, 2H), 4.32 (d, J=6.8 Hz, 2H),5.40-5.51 (m, 1H), 6.53 (d, J=6.2 Hz, 2H), 7.22 (d, J=7.2 Hz, 1H), 7.65(s, 1H), 7.82 (d, J=7.2 Hz, 1 Hz).

REFERENCE EXAMPLE 71 (7-Bromo-1-oxo-1H-isoquinolin-2-yl)acetaldehyde

¹H-NMR (CDCl₃) δppm:

4.77 (s, 2H), 6.52 (d, J=7.4 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 7.43 (d,J=8.5 Hz, 1H), 7.76 (dd, J=8.5 and 2.1 Hz, 1H), 8.55 (d, J=2.1 Hz, 1H),9.73 (s, 1H).

REFERENCE EXAMPLE 72(1-Oxo-5,6,7,8-tetrahydro-1H-isoquinolin-2-yl)acetaldehyde

¹H-NMR (CDCl₃) δppm:

1.73-1.94 (4H, m), 2.64-2.81 (2H, m), 2.81-2.98 (2H, m), 5.04-5.17 (2H,m), 6.72-6.84 (1H, m), 7.08 (1H, d, J=6.5 Hz), 8.31 (1H, d, J=6.5 Hz).

REFERENCE EXAMPLE 73 2-Butylpyridine-3-carbaldehyde

¹H-NMR (CDCl₃) δppm:

0.96 (3H, t, J=7.4 Hz), 1.41-1.48 (2H, m), 1.67-1.76 (2H, m), 3.21 (2H,t, J=8.0 Hz), 7.31 (1H, dd, J=7.8 and 4.8 Hz), 8.13 (1H, dd, J=7.8 and1.9 Hz), 8.72 (1H, dd, J=4.8 and 1.9 Hz), 10.36 (1H, s).

REFERENCE EXAMPLE 74 1-(Ethoxycarbonyl)cyclobutanecarboxylic acid

¹H-NMR (CDCl₃) δppm:

1.27 (t, J=7.1 Hz, 3H), 2.00-2.07 (m, 2H), 2.60 (t, J=8.2 Hz, 4H), 4.25(q, J=7.1 Hz, 1H).

REFERENCE EXAMPLE 75 Ethyl1-(2-aminophenylcarbamoyl)cyclobutanecarboxylate

¹H-NMR (CDCl₃) δppm:

1.34 (t, J=7.1 Hz, 3H), 1.97-2.08 (m, 2H), 2.60-2.68 (m, 2H), 2.71-2.82(m, 2H), 3.80 (br, 2H), 4.29 (q, J=7.1 Hz, 2H), 6.77-6.83 (m, 2H),7.02-7.08 (m, 1H), 7.95 (br, 1H).

REFERENCE EXAMPLE 76Spiro[benzo[b][1,4]diazepine-3,1′-cyclobutane]-2,4(1H,5H)-dione

¹H-NMR (DMSO-d₆) δppm:

1.59-1.70 (m, 2H), 3.29-3.44 (m, 4H), 7.07-7.14 (m, 4H), 10.4 (br, 2H).

REFERENCE EXAMPLE 771,5-Dimethylspiro[benzo[b][1,4]diazepine-3,1′-cyclobutane]-2,4(1H,5H)-dione

¹H-NMR (CDCl₃) δppm:

1.26-1.68 (m, 4H), 2.83-2.89 (m, 2H), 3.44 (s, 6H), 7.23-7.30 (m, 4H).

REFERENCE EXAMPLE 781,5-Dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[benzo[b][1,4]diazepine-3,1′-cyclobutane]-2,4(1H,5H)-dione

¹H-NMR (CDCl₃) δppm:

1.26 (s, 6H), 1.60 (s, 6H), 1.62-1.69 (m, 4H), 2.06-2.89 (m, 2H), 3.45(s, 3H), 3.48 (s, 3H), 7.26-7.28 (m, 1H), 7.65-7.70 (m, 2H).

REFERENCE EXAMPLE 797-Hydroxy-1,5-dimethylspiro[benzo[b][1,4]diazepine-3,1′-cyclobutane]-2,4(1H,5H)-dione

¹H-NMR (CDCl₃) δppm:

1.58-1.62 (m, 4H), 2.83-2.88 (m, 2H), 3.41 (s, 3H), 3.44 (s, 3H), 7.14(d, J=8.7 Hz, 1H), 7.36 (dd, J=8.7 and 2.1 Hz, 1H), 7.41 (d, J=2.1 Hz,1H).

EXAMPLE 457 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionesulfate

Sulfuric acid (13 μl) was added to an ethyl acetate solution (5 ml) of1-ethyl-3,3,5-trimethyl-7-(3-[(pyridin-4-ylmethyl)amino]propoxyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(100 mg, 0.24 mmol), and stirred at room temperature for 15 minutes. Theresultant mixture was concentrated to dryness under reduced pressure tothereby obtain 1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionesulfate as a white amorphous solid.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 0.99 (t, J=7.0 Hz, 3H), 1.31 (s, 3H), 2.14-2.18 (m, 2H),3.14-3.18 (m, 2H), 3.31 (s, 3H), 3.61-3.69 (m, 1H), 4.00-4.09 (m, 1H),4.10-4.14 (m, 2H), 4.27 (s, 2H).6.94-6.95 (m, 2H), 7.40 (d, J=9.0 Hz,1H), 7.55-7.57 (m, 2H), 8.62-8.64 (m, 2H).

EXAMPLE 458 Synthesis of1,3,3,5-tetramethyl-7-(3-{[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetris phosphate

85% phosphoric acid aqueous solution (0.34 ml) was added to an ethanolsolution (19 ml) of1,3,3,5-Tetramethyl-7-(3-{[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione(1.05 g, 1.84 mmol), and stirred at 50° C. for 15 minutes. The reactionmixture was cooled to room temperature. The precipitated insolublematter was collected by filtration, washed with ethanol, and dried tothereby obtain 1.59 g (yield: 73%) of1,3,3,5-Tetramethyl-7-(3-{[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dionetris(phosphate) as a white solid.

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.32 (3H, s), 1.78-1.98 (2H, m), 2.55-2.77 (4H, m),2.81-2.98 (2H, m), 3.28 (3H, s), 3.29 (3H, s), 3.51 (H, t, 6.6 Hz), 3.62(2H, m), 3.68(s, 2H), 3.99 (2H, t, J=6.0 Hz), 6.75 (2H, dd, J=2.6 and9.0 Hz), 6.82 (2H, d, 2.6 Hz), 7.21-7.38 (5H, m), 7.41-7.51 (1H, m),8.34 (2H, d, J=5.8 Hz)

EXAMPLE 459 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)isonicotinamide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC) (0.16g, 0.85 mmol) was added to an acetonitrile solution (6 ml) of1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.3 g, 0.71 mmol), isonicotinic acid (96 mg, 0.78 mmol), and1-hydroxybenzotriazole (HOBT) (0.138 g, 0.85 mmol), and then stirred atroom temperature for 2 days. The solvent was concentrated under reducedpressure. Ethyl acetate and a sodium hydrogen carbonate aqueous solutionwere added to the reaction mixture, and stirred for 1 hour. Water wasadded to the reaction mixture, and extraction with ethyl acetate wasconducted. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue thus obtained waspurified by medium pressure liquid chromatography (silica gel,dichloromethane:methanol=92:8). The purified product was concentratedunder reduced pressure and crystallized from ethyl acetate, diethyletherand n-hexane. The precipitated crystals were collected by filtration anddried to thereby obtain 0.21 g (yield:56%) ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)isonicotinamideas a white powder.

Melting Point 88.1 to 92.2° C.

EXAMPLE 460 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.88 (s, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.54 (s, 3H), 1.89-1.97 (m, 2H),2.74 (t, J=6.8 Hz, 2H), 2.83-2.95 (m, 2H), 3.39 (s, 3H), 3.69 (s, 2H),3.68-3.74 (m, 1H), 3.89 (t, J=6.0 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H),4.11-4.21 (m, 1H), 6.53-6.70 (m, 3H), 7.05 (d, J=7.2 Hz, 1H), 7.10 (d,J=5.9 Hz, 2H), 7.20 (d, J=8.9 Hz, 1H), 7.32 (d, J=5.3 Hz, 1H), 7.63 (d,J=5.3 Hz, 1H), 8.32 (d, J=5.9 Hz, 2H).

EXAMPLE 461 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.88 (s, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.54 (s, 3H), 1.89-1.97 (m, 2H),2.74 (t, J=6.8 Hz, 2H), 2.83-2.95 (m, 2H), 3.39 (s, 3H), 3.68-3.74 (m,3H), 3.90 (t, J=6.0 Hz, 2H), 4.05-4.21 (m, 3H), 6.56 (d, J=7.1 Hz, 1H),6.60-6.70 (m, 2H), 7.03-7.10 (m, 3H), 7.16-7.23 (m, 2H), 7.73 (d, J=5.2Hz, 1H), 8.31 (d, J=5.9 Hz, 2H).

EXAMPLE 462 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 93.8° C.

¹H-NMR (CDCl₃) δppm:

0.87 (s, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.82-1.95 (m, 2H),2.72 (t, J=6.8 Hz, 2H), 2.76-2.89 (m, 2H), 3.38 (s, 3H), 3.68 (s, 2H),3.63-3.78 (m, 1H), 3.87 (t, J=6.0 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H),4.11-4.20 (m, 1H), 6.43 (d, J=7.4 Hz, 1H), 6.60 (d, J=2.8 Hz, 1H), 6.67(dd, J=9.0 and 2.8 Hz, 1H), 6.96 (d, J=2.9 Hz, 1H), 7.05-7.11 (m, 3H),7.19 (d, J=9.0 Hz, 1H), 7.50 (d, J=2.9 Hz, 1H), 8.35 (d, J=6.0 Hz, 2H).

EXAMPLE 463 Synthesis of7-(3-{[2-(2-bromo-4-oxo-4H-furo[3,2-c]pyridine-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.1 Hz, 3H), 1.32 (s, 3H), 2.15 (br, 2H),2.95-3.40 (m, 2H), 3.32 (s, 3H), 3.61-3.73 (m, 3H), 4.01-4.09 (m, 3H),4.34 (br, 4H), 6.81 (br, 2H), 6.88 (br, 1H), 7.10 (s, 1H), 7.39 (d,J=9.0 Hz, 1H), 7.74 (br, 1H), 8.13 (br, 2H), 8.86 (br, 2H).

EXAMPLE 464 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.1 Hz, 3H), 1.32 (s, 3H), 2.00-2.22 (m, 2H),2.22 (s, 3H), 3.11-3.39 (m, 7H), 3.60-3.71 (m, 1H), 4.02-4.07 (m, 3H),4.30-4.45 (m, 2H), 4.51-4.71(m, 2H), 6.55 (s, 1H), 6.72 (d, J=7.3 Hz,1H), 6.84-6.90 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H),8.21 (br, 2H), 8.89 (br, 2H).

EXAMPLE 465 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (s, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.83-1.96 (m, 2H),2.42 (s, 3H), 2.72 (t, J=6.2 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 3.39 (s,3H), 3.68 (s, 2H), 3.66-3.79 (m, 1H), 3.89 (t, J=6.1 Hz, ²H), 4.08-4.23(m, 3H), 6.37 (d, J=7.3 Hz, 1H), 6.49-6.54 (m, 1H), 6.63-6.69 (m, 2H),7.01 (d, J=7.3 Hz, 1H), 7.08-7.12 (m, 2H), 7.19 (d, J=8.3 Hz, 1H),8.35-8.37 (m, 2H).

EXAMPLE 466 Synthesis of1-ethyl-7-(3-{[2-(2-ethyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-ethyl]-pyridin-4-ylmethyl-amino}-propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.5 Hz, 3H), 1.32 (s,3H), 2.09 (br, 2H), 2.87 (q, J=7.5 Hz, 2H), 3.10-3.21 (m, 2H), 3.30 (s,3H), 3.51-3.69 (m, 3H), 3.90-4.09 (m, 5H), 4.30 (br, 2H), 6.71-6.88 (m,3H), 7.18-7.20 (m, 1H), 7.36-7.43 (m, 1H), 7.52 (br, 1H), 7.86 (br, 2H),8.69 (br, 2H).

EXAMPLE 467 Synthesis of7-(3-{[2-(2,3-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

Pale Yellow Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.05-2.20 (m, 2H),2.17 (s, 3H), 2.29 (s, 3H), 3.05-3.20 (m, 2H), 3.31 (s, 3H), 3.61-3.73(m, 3H), 3.95-4.05 (m, 3H), 4.31 (br, 4H), 6.63 (br, 1H), 6.81-6.88 (m,2H), 7.39 (d, J=9.0 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 8.04 (br, 2H), 8.79(br, 2H).

EXAMPLE 468 Synthesis of1-ethyl-7-(3-{[2-(2-furan-3-yl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

A 2N-Sodium carbonate aqueous solution (0.3 ml) andtetrakis(triphenylphosphine)palladium(0) (37.2 mg, 0.03 mmol) were addedto a dimethoxyethane solution (2 ml) of7-(3-{[2-(2-bromo-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.20 g, 0.31 mmol) and furan-3-boronic acid (39.2 mg, 0.035 mmol), andstirred under argon atmosphere at 80° C. for 6.5 hours. The reactionmixture was cooled to room temperature, and purified by silica gelcolumn chromatography (ethyl acetate:methanol=100:0→93:7). The purifiedproduct was concentrated under reduced pressure and the resultantresidue was dissolved in ethyl acetate (10 ml). A 4N-HCl ethyl acetatesolution (0.5 ml) was added to the solution, and concentrated to drynessunder reduced pressure to thereby obtain 0.10 g (yield: 51%) of1-ethyl-7-(3-{[2-(2-furan-3-yl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride as a pale yellow amorphous solid.

¹H-NMR (DMSO-d₆) δppm:

0.73 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.09 (br, 2H),3.21-3.40 (m, 2H), 3.29 (s, 3H), 3.51-3.64 (m, 3H), 3.81-4.01 (m, 5H),4.30 (br, 2H), 6.78 (br, 2H), 6.84 (br, 1H), 6.98 (d, J=0.74 Hz, 1H),7.16 (s, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.69 (d, J=5.9 Hz, 1H), 7.82 (s,1H), 7.93 (br, 2H), 8.19 (s, 1H), 8.74 (br, 2H).

EXAMPLE 469 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-2-pyridin-3-yl-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 468, the object compound was synthesized.

Pale Yellow Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.73 (s, 3H), 0.99 (t, J=7.0 Hz, 3H), 1.31 (s, 3H), 2.13 (br, 2H),3.10-3.30 (m, 2H), 3.30 (s, 3H), 3.70-3.85 (m, 1H), 3.92-4.03 (m, 5H),4.38 (br, 4H), 6.80-6.87 (m, 3H), 7.35 (d, J=9.0 Hz, 1H), 7.79-7.84 (m,3H), 8.07 (br, 2H), 8.55 (d, J=8.0 Hz, 1H), 8.72 (dd, J=1.3, 5.2 Hz,1H), 8.82 (br, 2H), 9.23 (d, J=1.8 Hz, 1H).

EXAMPLE 470 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-2-pyridin-4-yl-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 468, the object compound was synthesized.

Yellow Powder

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 0.99 (t, J=7.0 Hz, 3H), 1.31 (s, 3H), 2.11 (br, 2H),3.12-3.30 (m, 2H), 3.29 (s, 3H), 3.55-3.69 (m, 1H), 3.91-4.08 (m, 5H),4.36 (br, 4H), 6.77-6.90 (m, 3H), 7.35 (d, J=8.9 Hz, 1H), 7.93 (br, 3H),8.30 (br, 3H), 8.76 (br, 2H), 8.91 (d, J=5.6 Hz, 2H).

EXAMPLE 471 Synthesis of7-[3-({2-[2-(3-amino-henyl)-4-oxo-4H-furo[3,2-c]pyridin-5-yl]ethyl}pyridin-4-ylmethylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 468, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.73 (s, 3H), 0.99 (t, J=7.0 Hz, 3H), 1.31 (s, 3H), 2.10 (br, 2H),3.02-3.20 (m, 2H), 3.30 (s, 3H), 3.55-3.70 (m, 1H), 3.95-4.03 (m, 5H),4.39 (br, 4H), 6.78-6.88 (m, 3H), 7.15-7.80 (m, 2H), 7.53 (br, 2H),7.62-7.81 (m, 3H), 8.06 (br, 2H), 8.82 (br, 2H).

EXAMPLE 472 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]pyridin-3-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 125° C.

EXAMPLE 473 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]quinolin-4-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.74 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.00-2.28 (2H, m),2.70-5.31 (15H, m), 6.45-6.59 (1H, m), 6.76-6.80 (1H, m), 6.83-6.87 (2H,m), 7.37 (1H, d, J=9.0 Hz) 7.42-7.58 (1H, m), 7.72-7.88 (1H, m),7.95-8.19 (3H, m), 8.31 (1H, d, J=8.6 Hz), 8.43-8.50 (1H, m), 9.03-9.19(1H, m)

EXAMPLE 474 Synthesis of1-ethyl-7-(3-{(3-hydroxybenzyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionehydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.12-2.27 (2H, m),3.20-3.44 (7H, m) 3.45-3.43 (2H, m), 3.63-3.70 (1H, m), 3.99-4.09 (3H,m), 4.35-4.37 (1H, m), 4.43-4.53 (1H, m) 6.68-6.71 (1H, m), 6.84-6.93(4H, m), 6.99-7.10 (2H, m), 7.20-7.26 (1H, m), 7.40 (1H, d, J=7.7 Hz),7.54-7.58 (1H, m), 8.17(1H, s), 9.72-9.80(1H, m)

EXAMPLE 475 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]thiazol-2-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.00 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.05-2.28 (2H, m),3.10-3.84(8H, m), 3.99-4.09 (3H, m), 4.40-4.50 (2H, m), 4.72-4.88 (2H,m), 6.64-6.67 (1H,m), 6.84-6.92 (3H,m), 7.39 (1H, d, J=9.0 Hz) 7.52-7.59(1H, m), 7.65-7.91 (2H, m), 8.14 (1H, d, J=1.9 Hz)

EXAMPLE 476 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-2-phenyl-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 468, the object compound was synthesized.

Amorphous

¹H-NMR (DMSO-d6) δppm:

0.72 (s, 3H), 0.99 (t, J=7.0 Hz, 3H), 1.31 (s, 3H), 2.09 (br, 2H),3.11-3.30 (m, 2H), 3.29 (s, 3H), 3.61-3.72 (m, 1H), 3.60-4.04 (m, 5H),4.38 (br, 4H), 6.71-6.88 (m, 3H), 7.32 (d, J=8.6 Hz, 1H), 7.37-7.41 (m,1H), 7.46-7.51 (m, 3H), 7.74 (br, 1H), 7.86 (d, J=7.4 Hz, 2H), 8.03 (br,2H), 8.81 (br, 2H).

EXAMPLE 477 Synthesis of1-ethyl-7-[3-({2-[2-(4-methoxyphenyl)-4-oxo-4H-furo[3,2-c]pyridin-5-yl]ethyl}pyridin-4-ylmethylamino)-propoxy]-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 468, the object compound was synthesized.

Amorphous

¹H-NMR (DMSO-d6) δppm:

0.71 (s, 3H), 0.98 (t, J=7.0 Hz, 3H), 1.31 (s, 3H), 2.00 (br, 2H), 3.28(s, 3H), 3.20-3.38 (m, 2H), 3.50-3.70 (m, 1H), 3.82 (s, 3H), 3.90-4.02(m, 5H), 4.40 (br, 4H), 6.82 (br, 3H), 7.05 (d, J=8.8 Hz, 2H), 7.30 (br,2H), 7.66 (br, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.92 (br, 2H), 8.68 (br,2H).

EXAMPLE 478 Synthesis of1-ethyl-3,3,5-trimethyl-7-[3-(pyridin-4-ylmethylpyridin-2-ylmethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

Colorless Oil

¹H-NMR (CDCl₃) δppm:

0.86 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.91-2.08 (m, 2H),2.66 (t, J=6.9 Hz, 2H), 3.39 (s, 3H), 3.61 (s, 2H), 3.63 (s, 2H),3.61-3.78 (m, 1H), 3.97 (t, J=6.1 Hz, 2H), 4.03-4.20 (m, 1H), 6.60 (d,J=2.7 Hz, 1H), 6.70 (dd, J=2.7 and 9.0 Hz, 1H), 7.16-7.26 (m, 4H),7.64-7.68 (m, 1H), 8.46-8.52 (m, 3H), 8.60 (br, 1H).

EXAMPLE 479 Synthesis of1-ethyl-3,3,5-trimethyl-7-[3-(pyridin-4-ylmethylpyridin-2-ylmethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

White solid

¹H-NMR (DMSO-d₆) δppm:

0.76 (s, 3H), 1.05 (t, J=7.0 Hz, 3H), 1.33 (s, 3H), 2.09 (br, 2H), 2.75(br, 2H), 3.31 (s, 3H), 3.61-3.73 (m, 1H), 4.03-4.30 (m, 5H), 4.53 (br,2H), 6.81-6.82 (m, 2H), 7.34-7.37 (m, 1H), 7.94 (br, 1H), 8.15 (br, 2H),8.64 (br, 1H), 8.80-8.87 (m, 3H), 9.01(Br, 1H).

EXAMPLE 480 Synthesis of1-ethyl-3,3,5-trimethyl-7-[3-(pyridin-4-ylmethylpyridin-3-ylmethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

Colorless Oil

¹H-NMR (CDCl₃) δppm:

0.86 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.91-2.04 (m, 2H),2.71 (t, J=6.9 Hz, 2H), 3.38 (s, 3H), 3.67 (s, 2H), 3.61-3.72 (m, 1H),3.80 (s, 2H), 3.99 (t, J=6.1 Hz, 2H), 4.05-4.20 (m, 1H), 6.61 (d, J=2.8Hz, 1H), 6.71 (dd, J=2.8 and 9.0 Hz, 1H), 7.14-7.19 (m, 2H), 7.26-7.31(m, 2H), 7.46 (d, J=7.8 Hz, 1H), 7.57-7.68 (m, 1H), 8.47-8.54 (m, 3H).

EXAMPLE 481 Synthesis of1-ethyl-3,3,5-trimethyl-7-[3-(pyridin-4-ylmethylpyridin-3-ylmethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.76 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.14 (br, 2H), 2.96(br, 2H), 3.30 (s, 3H), 3.61-3.73 (m, 1H), 4.03-4.10 (m, 3H), 4.27-4.32(m, 4H), 6.81-6.85 (m, 2H), 7.38 (d, J=9.0 Hz, 1H), 7.64 (br, 1H), 7.81(br, 1H), 8.07 (br, 3H), 8.81 (br, 3H).

EXAMPLE 482 Synthesis of7-[3-(bis-pyridin-4-ylmethylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

Colorless Oil

¹H-NMR (CDCl₃) δppm:

0.86 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.91-2.02 (m, 2H),2.66 (t, J=6.6 Hz, 2H), 3.38 (s, 3H), 3.62 (s, 4H), 3.61-3.78 (m, 1H),3.92-3.99 (m, 2H), 4.01-4.20 (m, 1H), 6.61 (d, J=2.8 Hz, 1H), 6.70 (dd,J=2.8 and 9.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.28-7.30 (m, 4H),8.50-8.53 (m, 4H).

EXAMPLE 483 Synthesis of7-[3-(bis-pyridin-4-ylmethylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.02 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.01 (br, 2H), 2.67(br, 2H), 3.30 (s, 3H), 3.63-3.72 (m, 1H), 4.03-4.10 (m, 7H), 6.81-6.85(m, 2H), 7.37 (d, J=9.0 Hz, 1H), 8.10 (br, 4H), 8.84 (br, 4H).

EXAMPLE 484 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(5-methylfuran-2-ylmethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

Pale Yellow Oil

¹H-NMR (CDCl₃) δppm:

0.86 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.91-2.05 (m, 2H),2.27 (s, 3H), 2.67 (t, J=6.6 Hz, 2H), 3.39 (s, 3H), 3.63 (s, 2H), 3.64(s, 2H), 3.62-3.79 (m, 1H), 4.02 (t, J=6.2 Hz, 2H), 4.07-4.22 (m, 1H),5.87 (br, 1H), 6.04 (br, 1H), 6.66 (d, J=2.8 Hz, 1H), 6.75 (dd, J=2.8and 9.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.24-7.26 (m, 2H), 8.46-8.50(m, 2H).

EXAMPLE 485 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(5-methylfuran-2-ylmethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

Pale Yellow Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.76 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.21-2.30 (m, 5H),3.05 (br, 2H), 3.32 (s, 3H), 3.62-3.72 (m, 1H), 4.02-4.11 (m, 3H),4.23-4.58 (m, 4H), 6.10 (br, 1H), 6.57 (br, 1H), 6.87-6.91 (m, 2H), 7.40(d, J=9.0 Hz, 1H), 8.20 (br, 2H), 8.90 (br, 2H).

EXAMPLE 486 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-methylamino-ethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 44, the object compound was synthesized.

¹H-NMR (DMSO-d6) δppm:

0.76 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.21 (br, 2H), 2.51(s, 3H), 3.10 (br, 2H), 3.33 (s, 3H), 3.35 (br, 2H), 3.61-3.72 (m, 1H),4.00-4.12 (m, 5H), 4.55 (br, 2H), 6.90 (dd, J=2.6, 9.0 Hz, 1H), 6.94 (d,J=2.6 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 8.35 (br, 2H), 8.95 (br, 2H),9.50 (br, 2H).

EXAMPLE 487 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylbenzamide

Diethyl phosphorocyanidate (0.15 g, 1.0 mmol) was added to a THFsolution (5 ml) of1-ethyl-3,3,5-trimethyl-7-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.39 g, 0.83 mmol), benzoic acid (0.14 g, 1.1 mmol), and triethylamine(0.15 ml, 1.1 mmol), and the mixture was stirred at room temperatureovernight. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate:methanol=100:0→80:20). The purifiedproduct was concentrated under reduced pressure to thereby obtain 0.41 g(yield: 86%) ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methyl-benzamide as a colorless oil.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.86-1.98 (m, 2H),2.72 (br, 4H), 2.93 (br, 3H), 3.36 (s, 3H), 3.40-3.69 (m, 5H), 3.98 (br,2H), 4.13-4.23 (m, 1H), 6.66 (d, J=2.8 Hz, 1H), 6.70 (dd, J=2.8 and 9.0Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 7.17-7.27 (m, 2H), 7.30-7.39 (m, 5H),8.47-8.50 (m, 2H).

EXAMPLE 488 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.33 (s, 3H), 2.38 (br, 2H), 2.97(s, 3H), 3.32 (br, 5H), 3.40-3.49 (m, 2H), 3.61-3.70 (m, 1H), 3.97 (br,2H), 4.01-4.10 (m, 1H), 4.15 (br, 2H), 4.87 (br, 2H), 6.90-6.95 (m, 2H),7.40-7.49 (m, 6H), 8.50 (br, 2H), 9.05 (br, 2H).

EXAMPLE 489 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-3-methoxy-N-methylbenzamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.92 (br, 2H), 2.71(br, 4H), 2.93 (br, 3H), 3.36 (s, 3H), 3.40-3.80 (m, 5H), 3.79 (s, 3H),3.99 (br, 2H), 4.08-4.25 (m, 1H), 6.67 (d, J=2.8 Hz, 1H), 6.72 (dd,J=2.8 and 9.0 Hz, 1H), 6.85-6.94 (m, 3H), 7.16 (d, J=9.0 Hz, 1H),7.12-7.30 (m, 3H), 8.47-8.50 (m, 2H).

EXAMPLE 490 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-3-methoxy-N-methylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (br, 3H), 1.00 (br, 3H), 1.32 (s, 3H), 2.33 (br, 2H), 2.94 (s, 3H),3.30 (br, 7H), 3.61-3.70 (m, 1H), 3.77 (s, 3H), 4.01-4.15 (m, 5H), 4.71(br, 2H), 6.91 (br, 2H), 7.02 (br, 3H), 7.32-7.41 (m, 2H), 8.17 (br,2H), 8.89 (br, 2H).

EXAMPLE 491 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-4-methoxy-N-methylbenzamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.51 (s, 3H), 1.84-1.97 (m, 2H),2.60-2.78 (m, 4H), 2.95 (s, 3H), 3.37 (s, 3H), 3.50-3.75 (m, 5H), 3.82(s, 3H), 4.00 (t, J=6.2 Hz, 2H), 4.08-4.21 (m, 1H), 6.67 (d, J=2.8 Hz,1H), 6.86 (dd, J=2.8 and 9.0 Hz, 1H), 6.85-6.88 (m, 2H), 7.16 (d, J=9.0Hz, 1H), 7.17-7.21 (m, 2H), 7.32-7.33 (m, 2H), 8.47-8.50 (m, 2H).

EXAMPLE 492 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-4-methoxy-N-methylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (br, 3H), 1.00 (br, 3H), 1.32 (s, 3H), 2.32 (br, 2H), 2.99 (s, 3H),3.30 (br, 5H), 3.66 (br, 2H), 3.78 (s, 3H), 3.88 (br, 3H), 4.10 (br,3H), 4.64 (br, 2H), 6.87-6.97 (m, 4H), 7.38-7.45 (m, 3H), 8.12 (br, 2H),8.95 (br, 2H).

EXAMPLE 493 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2-fluoro-N-methylbenzamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.51 (s, 3H), 1.95-2.04 (m, 2H),2.43-2.59 (m, 2H), 2.81-2.95 (m, 2H), 2.83 (s, 3H), 3.35 (s, 3H),3.62-3.79 (m, 5H), 4.02-4.21 (m, 3H), 6.61-6.79 (m, 3H), 7.00-7.39 (m,6H), 8.46-8.49 (m, 2H).

EXAMPLE 494 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2-fluoro-N-methylbenzamide

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (br, 3H), 1.00 (br, 3H), 1.32 (s, 3H), 2.32 (br, 2H), 2.88 (s, 3H),3.30 (br, 5H), 3.68 (br, 3H), 4.12 (br, 5H), 4.72 (br, 2H), 6.89-6.93(m, 2H), 7.29 (br, 2H), 7.38-7.42 (m, 1H), 7.51 (br, 2H), 8.29 (br, 2H),8.96 (br, 2H).

EXAMPLE 495 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2,N-dimethylbenzamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.49 (s, 3H), 1.95-2.04 (m, 2H),2.26 (s, 3H), 2.43-2.59 (m, 2H), 2.73 (s, 3H), 2.72-2.81 (m, 2H), 3.35(s, 3H), 3.62-3.79 (m, 5H), 4.02-4.27 (m, 3H), 6.60-6.79 (m, 2H),7.00-7.35 (m, 7H), 8.46-8.52 (m, 2H).

EXAMPLE 496 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2,N-dimethylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (br, 3H), 1.32 (s, 3H), 2.18 (s, 3H), 2.33 (br, 2H),2.78 (s, 3H), 3.30 (br, 5H), 3.60-3.75 (m, 3H), 4.04-4.08 (m, 3H),4.13(br, 2H), 4.71 (br, 2H), 6.87-6.93 (m, 2H), 7.15-7.31 (m, 4H),7.40-7.42 (m, 1H), 8.23 (br, 2H), 8.92 (br, 2H).

EXAMPLE 497 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-4,N-dimethylbenzamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.51 (s, 3H), 1.84-1.98 (m, 2H),2.35 (s, 3H), 2.60-2.78 (m, 4H), 2.93 (s, 3H), 3.36 (s, 3H), 3.53-3.78(m, 5H), 4.00 (br, 2H), 4.07-4.22 (m, 1H), 6.67 (d, J=2.8 Hz, 1H), 6.70(dd, J=2.8 and 9.0 Hz, 1H), 7.10-7.17 (m, 3H), 7.20-7.27 (m, 4H),8.47-8.50 (m, 2H).

EXAMPLE 498

Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-4,N-dimethylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (br, 3H), 1.32 (s, 3H), 2.32 (br, 5H), 2.95 (s, 3H),3.30 (br, 5H), 3.60-3.75 (m, 3H), 3.80-4.15 (m, 5H), 4.68 (br, 2H),6.91(br, 2H), 7.23 (br, 2H), 7.40-7.42 (m, 3H), 8.23 (br, 2H), 8.91 (br,2H).

EXAMPLE 499 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2-(2-methoxyphenyl)-N-methylacetamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s; 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.84-1.99 (m, 2H),2.60-2.73 (m, 4H), 3.04 (s, 3H), 3.37 (s, 3H), 3.41-3.53 (m, 2H), 3.65(br, 2H), 3.61-3.70 (m, 1H), 3.83 (s, 3H), 3.93-4.00 (m, 2H), 4.06-4.21(m, 1H), 4.68 (s, 2H), 6.63-6.73 (m, 2H), 6.80-6.97(m, 4H), 7.10-7.24(m, 3H), 8.47-8.49 (m, 2H).

EXAMPLE 500 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2-(2-methoxyphenyl)-N-methylacetamide dihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.31 (s, 3H), 2.25 (br, 2H), 3.04(s, 3H), 3.30 (br, 5H), 3.40-3.49 (m, 2H), 3.75 (s, 3H), 3.75 (br, 1H),3.94-4.08 (m, 5H), 4.67 (br, 2H), 4.83 (s, 2H), 6.79-6.99 (m, 6H), 3.78(d, J=9.0 Hz, 1H), 8.05 (br, 2H), 8.83 (br, 2H).

EXAMPLE 501 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2-(3-methoxyphenyl)-N-methylacetamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.82-1.93 (m, 2H),2.60-2.73 (m, 4H), 2.91 (s, 3H), 3.37 (s, 3H), 3.41-3.54 (m, 2H),3.59-3.70 (m, 5H), 3.76 (s, 3H), 3.97 (t, J=6.1 Hz, 2H), 4.06-4.21 (m,1H), 6.65-6.81 (m, 5H), 7.13-7.25 (m, 4H), 8.44-8.50 (m, 2H).

EXAMPLE 502 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2-(3-methoxyphenyl)-N-methylacetamide dihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.24 (br, 2H), 3.03(s, 3H), 3.23 (br, 2H), 3.30 (s, 3H), 3.63-3.72 (m, 6H), 4.01-4.08 (m,5H), 4.62 (br, 4H), 6.78-6.91 (m, 5H), 7.20 (t, J=7.8 Hz, 1H), 7.39 (d,J=8.9 Hz, 1H), 8.22 (br, 2H), 8.90 (br, 2H).

EXAMPLE 503 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2-(4-methoxyphenyl)-N-methylacetamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.82-1.93 (m, 2H),2.57-2.73 (m, 4H), 2.91 (s, 3H), 3.37 (s, 3H), 3.43-3.54 (m, 2H), 3.59(s, 2H), 3.60-3.75 (m, 3H), 3.76 (s, 3H), 3.97 (t, J=6.1 Hz, 2H),4.06-4.21 (m, 1H), 6.65 (br, 1H), 6.73 (dd, J=8.9 and 2.8 Hz, 1H), 6.83(d, J=8.4 Hz, 2H), 7.05-7.21 (m, 5H), 8.44-8.50 (m, 2H).

EXAMPLE 504 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2-(4-methoxyphenyl)-N-methylacetamide dihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.31 (s, 3H), 2.27 (br, 2H), 3.04(s, 3H), 3.23 (br, 2H), 3.30 (s, 3H), 3.63-3.72 (m, 6H), 4.01-4.08 (m,5H), 4.62 (br, 4H), 6.78-6.89 (m, 4H), 7.12-7.14 (m, 2H), 7.39 (d, J=9.0Hz, 1H), 7.96 (br, 2H), 8.81 (br, 2H).

EXAMPLE 505 Synthesis of2-benzo[1,3]dioxol-5-yl-N-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylacetamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.82-1.93 (m, 2H),2.57-2.73 (m, 4H), 2.92 (s, 3H), 3.37 (s, 3H), 3.41-3.50 (m, 2H), 3.57(s, 2H), 3.59-3.73 (m, 3H), 3.98 (t, J=6.1 Hz, 2H), 4.07-4.20 (m, 1H),5.89 (s, 2H), 6.64-6.77 (m, 5H), 7.07-7.25 (m, 3H), 8.44-8.49 (m, 2H).

EXAMPLE 506 Synthesis of2-benzo[1,3]dioxol-5-yl-N-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylacetamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.25 (br, 2H), 3.03(s, 3H), 3.23 (br, 2H), 3.30 (s, 3H), 3.63-3.71 (m, 3H), 4.01-4.08 (m,5H), 4.58 (br, 2H), 4.69 (br, 2H), 5.97 (s, 2H), 6.67-6.69 (m, 1H),6.80-6.83 (m, 2H), 6.89-6.91 (m, 2H), 7.39 (d, J=8.9 Hz, 1H), 8.14 (br,2H), 8.87 (br, 2H).

EXAMPLE 507 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(3-methylpyridin-4-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-amino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.02 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.90-2.01 (2H, m),2.35-2.45 (3H, m), 2.61-3.95 (8H, m), 3.96-4.32 (7H, m), 6.49-6.61 (1H,m), 6.81-6.89 (3H, m), 7.39 (1H, d, J=9.0 Hz), 7.41-7.51 (1H, m),7.52-8.02 (1H, m), 8.11 (1H, s), 8.41-8.49 (1H, m), 8.65 (1H, s)

EXAMPLE 508 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-4-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.82-2.11 (2H, m),2.61-3.81 (8H, m), 3.89-4.41 (10H, m), 6.54-6.59 (1H, m), 6.78-6.91 (3H,m), 7.39 (1H, d, J=9.0 Hz), 7.48-7.53 (1H, m), 7.52-7.99 (2H, m), 8.12(1H, s), 8.52-8.68 (1H, m)

EXAMPLE 509 Synthesis of1-ethyl-7-(3-{(3-fluoropyridin-4-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.99-2.27 (2H, m),3.31 (3H, s), 3.33-3.81 (5H,m), 3.96-4.20 (3H, m), 4.25-4.45 (4H, m),6.60-6.64 (1H, m), 6.80-6.92 (3H, m), 7.39 (1H, d, J=9.0 Hz), 7.52-7.56(1H, m), 7.57-8.12 (1H, m), 8.14 (1H, s), 8.15-8.57 (1H, m), 8.60-8.66(1H, m)

EXAMPLE 510 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.90-2.17 (2H, m),2.52-3.00 (4H, m), 3.25-3.94 (9H, m), 4.01-4.35 (5H, m), 6.52-6.60 (1H,m), 6.82-6.91 (3H, m), 6.93-7.38 (1H, m), 7.40 (1H, d, J=9.0 Hz),7.47-7.94 (2H, m), 8.12 (1H, s), 8.60-8.68 (1H, m)

EXAMPLE 511 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-(4-trifluoromethylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 137 to 138° C.

EXAMPLE 512 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-(2-pyrrolidin-1-ylpyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.91-2.03 (5H, m),3.27-3.76 (13H,m), 3.99-4.61 (7H, m), 6.58-6.62 (1H,m), 6.91-7.24 (4H,m), 7.40 (1H, d, J=9.1 Hz), 7.43-8.09 (3H, m), 8.13 (1H, s)

EXAMPLE 513 Synthesis of2-({[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-benzonitrilephosphate

Using an appropriate starting material and following the procedure ofExample 7 and Example 458, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.02 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.78-1.90 (2H, m),2.65 (2H, t, J=6.5 Hz), 2.77 (2H, t, J=5.7 Hz), 3.30 (3H, s), 3.34-4.13(8H, m), 6.46 (1H, d, J=6.7 Hz), 6.74 (1H, dd, J=2.7 and 9.0 Hz), 6.81(1H, d, J=2.7 Hz), 6.85 (1H, d, J=2.0 Hz), 7.21-7.32 (3H, m), 7.35-7.40(2H, m), 7.63 (1H, m), 8.07 (1H, d, J=2.0 Hz)

EXAMPLE 514 Synthesis of7-(3-{(3,5-dihydroxybenzyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionehydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.00 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.20-2.35 (2H, m),3.08-3.62 (7H, m), 3.63-3.72 (1H, m), 3.99-4.17(3H, m), 4.18-4.28 (1H,m), 4.30-4.72 (3H, m), 6.34 (1H, s), 6.45 (2H, s), 6.70 (1H, d, J=7.0Hz), 6.86-6.96 (3H, m), 7.39 (1H, d, J=8.9 Hz), 7.56 (1H, d, J=7.1 Hz),8.16 (1H, s), 9.47 (2H, br s)

EXAMPLE 515 Synthesis of1-ethyl-7-(3-{(5-fluoropyridin-3-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionehydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.00 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.17-2.32 (2H, m),3.22-3.73 (8H, m), 3.99-4.10 (3H, m), 4.44-4.66(4H, m), 6.68 (1H, d,J=7.0 Hz), 6.85-6.93 (3H, m), 7.41 (1H, d, J=9.0 Hz), 7.58 (1H, d, J=7.0Hz), 8.05-8.21 (2H, m), 8.64-8.71 (2H, m)

EXAMPLE 516 Synthesis of1-ethyl-7-(2-hydroxy-3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

Colorless Solid

Melting Point 67 to 74° C.

EXAMPLE 517 Synthesis of1-ethyl-7-(2-hydroxy-3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-3-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

Colorless Solid

¹H-NMR (DMSO-D₆) δppm:

0.74 (3H, s), 1.03 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.54-3.08 (3H, m),3.23-3.30 (3H, m), 3.49-3.92 (6H, m), 3,92-4.27 (3H, m), 4.84-4.99 (1H,m), 6.45-6.56 (1H, m), 6.56-6.79 (2H, m), 6.88-7.06 (1H, m), 7.22-7.38(1H, m), 7.38-7.73 (5H,m), 8.16 (1H, d, J=8.1 Hz), 8.23-8.35 (1H, m),8.42′(1H, s).

EXAMPLE 518 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-3-fluoro-N-methylbenzamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 2.02 (br, 2H), 2.73(br, 4H), 2.92 (s, 3H), 3.36 (s, 3H), 3.41-3.73 (m, 5H), 3.99 (br, 2H),4.07-4.20 (m, 1H), 6.67 (d, J=2.8 Hz, 1H), 6.72 (dd, J=2.8 and 9.0 Hz,1H), 7.03-7.40 (m, 7H), 8.48-8.51 (m, 2H).

EXAMPLE 519 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-3-fluoro-N-methylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.33 (br, 2H), 2.93(s, 3H), 3.30 (br, 5H), 3.61-3.71 (m, 3H), 4.01-4.11 (m, 5H), 4.66 (br,2H), 6.88-6.91 (m, 2H), 7.28-7.33 (m, 2H), 7.39-7.40 (m, 2H), 7.46-7.52(m, 1H), 8.14 (br, 2H), 8.91 (br, 2H).

EXAMPLE 520 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-4-fluoro-N-methylbenzamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.95 (br, 2H), 2.73(br, 4H), 2.94 (s, 3H), 3.37 (s, 3H), 3.42-3.77 (m, 5H), 3.98 (br, 2H),4.07-4.20 (m, 1H), 6.67 (d, J=2.8 Hz, 1H), 6.72 (dd, J=2.8 and 9.0 Hz,1H), 7.05 (t, J=8.6 Hz, 2H), 7.16 (d, J=9.0 Hz, 1H), 7.26 (br, 2H),7.32-7.38 (m, 2H), 8.48-8.51 (m, 2H).

EXAMPLE 521 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-4-fluoro-N-methylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.27 (br, 2H), 2.94(s, 3H), 3.30 (br, 5H), 3.61-3.91 (m, 5H), 4.03-4.10 (m, 3H), 4.62 (br,2H), 6.86-6.90 (m, 2H), 7.24-7.26 (m, 2H), 7.39 (d, J=8.9 Hz, 1H), 7.56(br, 2H), 8.00 (br, 2H), 8.82 (br, 2H).

EXAMPLE 522 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-3,N-dimethylbenzamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.97 (br, 2H), 2.34(s, 3H), 2.78 (br, 4H), 2.94 (s, 3H), 3.36 (s, 3H), 3.43-3.81 (m, 5H),4.04 (br, 2H), 4.07-4.20 (m, 1H), 6.67 (d, J=2.8 Hz, 1H), 6.73 (dd,J=2.8 and 9.0 Hz, 1H), 7.09-7.26 (m, 5H), 7.32 (br, 2H), 8.48-8.51 (m,2H).

EXAMPLE 523 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-3,N-dimethylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.32 (br, 5H), 2.94(s, 3H), 3.30 (br, 5H), 3.61-3.91 (m, 5H), 4.02-4.11 (m, 3H), 4.62 (br,2H), 6.89-6.90 (m, 2H), 7.20-7.31 (m, 4H), 7.39 (d, J=8.9 Hz, 1H), 8.05(br, 2H), 8.83 (br, 2H).

EXAMPLE 524 Synthesis of2-dimethylamino-N-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylbenzamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.99 (br, 2H), 2.76(s, 6H), 2.74-2.89 (m, 4H), 3.06 (s, 3H), 3.36 (s, 3H), 3.53-3.83 (m,5H), 3.95-4.21 (m, 3H), 6.67-6.75 (m, 2H), 6.85-6.97 (m, 2H), 7.10-7.24(m, 3H), 7.40-7.42 (m, 2H), 8.53-8.55 (m, 2H).

EXAMPLE 525 Synthesis of2-dimethylamino-N-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylbenzamidetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.32 (br, 2H), 2.84(s, 6H), 2.94 (s, 3H), 3.01 (br, 7H), 3.64-3.70 (m, 1H), 3.93 (br, 2H),4.03-4.14 (m, 3H), 4.69 (br, 2H), 6.85-6.93 (m, 2H), 7.12 (br, 1H), 7.23(br, 2H), 7.39-7.42 (m, 2H), 8.22 (br, 2H), 8.92 (br, 2H).

EXAMPLE 526 Synthesis of3-dimethylamino-N-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylbenzamidetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-d6) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.34 (br, 2H), 2.96(s, 3H), 3.05 (s, 6H), 3.31 (s, 3H), 3.43 (br, 2H), 3.58-3.69 (m, 1H),3.94 (br, 2H), 4.01-4.10 (m, 1H), 4.13 (br, 2H), 4.68 (br, 2H), 4.81(br, 2H), 6.88-6.93 (m, 2H), 7.18 (br, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.47(br, 3H), 8.47 (br, 2H), 9.03 (br, 2H).

EXAMPLE 527 Synthesis of4-dimethylamino-N-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylbenzamidetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

White Solid

¹H-NMR (DMSO-d6) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.31 (br, 2H), 3.00(br, 9H), 3.22-3.48 (m, 4H), 3.31 (s, 3H), 3.61-3.70 (m, 1H), 3.89 (br,2H), 3.99-4.14 (m, 3H), 4.80 (br, 2H), 6.87-6.93 (m, 2H), 7.12 (br, 2H),7.40 (d, J=9.0 Hz, 1H), 7.48 (br, 2H), 8.46 (br, 2H), 9.03 (br, 2H).

EXAMPLE 528 Synthesis of furan-2-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.54 (s, 3H), 1.88-1.96 (m, 2H),2.65-2.80 (m, 4H), 3.14 (s, 3H), 3.39 (s, 3H), 3.61-3.75 (m, 5H), 4.01(t, J=6.2 Hz, 2H), 4.04-4.22 (m, 1H), 6.45-6.48 (m, 1H), 6.67-6.69 (m,1H), 6.73 (dd, J=2.8 and 9.0 Hz, 1H), 6.99 (d, J=3.5 Hz, 1H), 7.18 (d,J=9.0 Hz, 1H), 7.24-7.26 (m, 2H), 7.60 (br, 1H), 8.49-8.50 (m, 2H).

EXAMPLE 529 Synthesis of furan-2-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.29 (br, 2H),3.10-3.40 (m, 2H), 3.32 (s, 3H), 3.59-3.70 (m, 1H), 3.80-4.11 (m, 7H),4.70 (br, 2H), 6.63 (d, J=1.6 Hz, 1H), 6.88 (dd, J=2.7, 9.0 Hz, 1H),6.92 (d, J=2.7 Hz, 1H), 6.96 (d, J=3.3 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H),7.86 (br, 1H), 8.38 (br, 2H), 8.94 (br, 2H).

EXAMPLE 530 Synthesis of thiophene-2-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.54 (s, 3H), 1.86-1.96 (m, 2H),2.63-2.80 (m, 4H), 3.14 (s, 3H), 3.38 (s, 3H), 3.62-3.77 (m, 5H), 4.01(t, J=6.2 Hz, 2H), 4.03-4.20 (m, 1H), 6.67 (d, J=2.8 Hz, 1H), 6.73 (dd,J=2.8 and 9.0 Hz, 1H), 7.01-7.03 (m, 1H), 7.16 (d, J=9.0 Hz, 1H),7.24-7.26 (m, 2H), 7.30-7.32 (m, 1H), 7.59-7.61 (m, 1H), 8.48-8.50 (m,2H).

EXAMPLE 531 Synthesis of thiophene-2-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide dihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.26 (br, 3H), 3.23(br, 2H), 3.31 (s, 3H); 3.64-3.70 (m, 3H), 3.80-3.93 (m, 2H), 4.02-4.08(m, 3H), 4.59 (br, 2H), 6.85-6.89 (m, 2H), 7.14 (br, 1H), 7.39 (d, J=8.9Hz, 1H), 7.58 (br, 1H), 7.79 (br, 1H), 7.95 (br, 2H), 8.80 (br, 2H).

EXAMPLE 532 Synthesis of furan-3-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.87-1.98 (m, 2H),2.63-2.80 (m, 4H), 3.05 (s, 3H), 3.37 (s, 3H), 3.53-3.70 (m, 5H), 3.99(t, J=6.2 Hz, 2H), 4.01-4.21 (m, 1H), 6.56 (s, 1H), 6.66 (d, J=2.8 Hz,1H), 6.72 (dd, J=2.8 and 9.0 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 7.24-7.26(m, 2H), 7.39 (br, 1H), 7.66 (br, 1H), 8.47-8.50 (m, 2H).

EXAMPLE 533 Synthesis of furan-3-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide dihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.26 (br, 2H), 3.14(br, 3H), 3.31 (s, 5H), 3.62-3.70 (m, 3H), 3.87 (br, 2H), 4.03-4.09 (m,3H), 4.61 (br, 2H), 6.74 (br, 1H), 6.85-6.90 (m, 2H), 7.39 (d, J=8.9 Hz,1H), 7.74 (s, 1H), 8.09 (br, 2H), 8.14 (br, 1H), 8.85 (br, 2H).

EXAMPLE 534 Synthesis of thiophene-3-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.88-1.97 (m, 2H),2.62-2.78 (m, 4H), 3.00 (s, 3H), 3.37 (s, 3H), 3.51-3.73 (m, 5H), 3.99(t, J=6.2 Hz, 2H), 4.01-4.21 (m, 1H), 6.66 (d, J=2.8 Hz, 1H), 6.71 (dd,J=2.8 and 9.0 Hz, 1H), 7.13-7.26 (m, 4H), 7.26-7.29 (m, 1H), 7.43-7.44(m, 1H), 8.48-8.50 (m, 2H).

EXAMPLE 535 Synthesis of thiophene-3-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide dihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.28 (br, 2H), 3.06(br, 5H), 3.31 (s, 3H), 3.61-3.70 (m, 3H), 3.87 (br, 2H), 4.03-4.09 (m,3H), 4.61 (br, 2H), 6.86-6.90 (m, 2H), 7.28 (br, 1H), 7.39 (d, J=8.9 Hz,1H), 7.58-7.60 (m, 1H), 7.91 (br, 1H), 8.06 (br, 2H), 8.84 (br, 2H).

EXAMPLE 536 Synthesis of cyclohexanecarboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.83 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.50-1.81 (m, 10H),1.88-2.00 (m, 2H), 2.39 (br, 1H), 2.60-2.78 (m, 4H), 2.93 (s, 3H), 3.37(s, 3H), 3.43 (br, 2H), 3.61-3.74 (m, 3H), 3.91-4.21 (m, 3H), 6.67 (d,J=2.8 Hz, 1H), 6.73 (dd, J=2.8 and 9.0 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H),7.24-7.26 (m, 2H), 8.48 (br, 2H).

EXAMPLE 537 Synthesis of cyclohexanecarboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide dihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.08-1.28 (m, 6H), 1.32 (s, 3H),1.66 (br, 4H), 2.26 (br, 2H), 2.55 (br, 1H), 3.03 (s, 3H), 3.21 (br,2H), 3.32 (s, 3H), 3.64-3.71 (m, 3H), 4.02-4.10 (m, 5H), 4.59 (br, 2H),6.87-6.92 (m, 2H), 7.40 (d, J=8.9 Hz, 1H), 8.09 (br, 2H), 8.86 (br, 2H).

EXAMPLE 538 Synthesis of benzo[1,3]dioxole-5-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (s, 3H), 1.13 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.88-1.94 (m, 2H),2.62-2.75 (m, 4H), 2.94 (s, 3H), 3.36 (s, 3H), 3.51 (br, 2H), 3.63 (s,2H), 3.61-3.77 (m, 1H), 3.98 (t, J=6.2 Hz, 2H), 3.95-4.20 (m, 1H), 5.96(s, 2H), 6.67 (d, J=2.8 Hz, 1H), 6.72-6.79 (m, 2H), 6.83-6.88 (m, 2H),7.15 (d, J=9.0 Hz, 1H), 7.24-7.26 (m, 2H), 8.47-8.50 (m, 2H).

EXAMPLE 539 Synthesis of benzo[1,3]dioxole-5-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.32 (br, 2H), 2.95(s, 3H), 3.31 (br, 5H), 3.62-3.71 (m, 3H), 4.02-4.09 (m, 5H), 4.71 (br,2H), 6.06 (s, 2H), 6.86-7.06 (m, 5H), 7.39 (d, J=8.9 Hz, 1H), 8.29 (br,2H), 8.94 (br, 2H).

EXAMPLE 540 Synthesis of1-Ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo-2H-pyridin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

Light Brown Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.26 (br, 2H), 3.24(br, 2H), 3.32 (s, 3H), 3.64-3.73 (m, 1H), 4.01-4.09 (m, 5H), 4.37 (br,2H), 4.70 (br, 2H), 6.28 (t, J=6.5 Hz, 1H), 6.41 (d, J=9.0 Hz, 1H), 6.89(dd, J=2.5, 9.0 Hz, 1H), 6.93 (d, J=2.5 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H),7.42-7.47 (m, 1H), 7.78 (d, J=6.5 Hz, 1H), 8.34 (br, 2H), 8.98 (br, 2H).

EXAMPLE 541 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-2-methoxy-N-methylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.33 (br, 2H), 2.79(s, 3H), 3.21-3.44 (m, 2H), 3.30 (s, 3H), 3.53-3.64 (m, 1H), 3.94 (s,3H), 3.90-4.15 (m, 7H), 4.76 (br, 2H), 6.84-7.14 (m, 4H), 7.22 (d, J=7.4Hz, 1H), 7.38-7.44 (m, 2H), 8.36 (br, 2H), 8.99 (br, 2H).

EXAMPLE 542 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methyl-2-trifluoromethyl-benzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

Pale Yellow Powder

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.36 (br, 2H), 2.78(s, 3H), 3.30-3.43 (m, 5H), 3.61-3.70 (m, 1H), 3.85 (br, 2H), 4.00-4.19(m, 5H), 4.81 (br, 2H), 6.84-6.95 (m, 2H), 7.40 (d, J=9.0 Hz, 1H),7.62-7.69 (m, 2H), 7.76 (t, J=7.7 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 8.44(br, 2H), 9.01 (br, 2H).

EXAMPLE 543 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methyl-3-trifluoromethyl-benzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

Pale Yellow Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.36 (br, 2H), 2.95(s, 3H), 3.25-3.33 (m, 2H), 3.31 (s, 3H), 3.37-3.45 (m, 2H), 3.61-3.73(m, 1H), 3.97 (br, 2H), 4.00-4.13 (m, 1H), 4.13 (br, 2H), 4.82 (br, 2H),6.89-6.94 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H),7.82-7.86 (m, 2H), 7.91 (s, 1H), 8.47 (br, 2H), 9.02 (br, 2H).

EXAMPLE 544 Synthesis of2-cyano-N-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methyl-benzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.31 (br, 2H), 2.89(s, 3H), 3.16-3.45 (m, 2H), 3.30 (s, 3H), 3.50-3.75 (m, 3H), 3.90-4.15(m, 5H), 4.71 (br, 2H), 6.82-6.94 (m, 2H), 7.40 (d, J=9.0 Hz, 1H),7.62-7.67 (m, 1H), 7.74 (br, 1H), 7.78-7.80 (m, 1H), 7.95 (d, J=7.7 Hz,1H), 8.29 (br, 2H), 8.94 (br, 2H).

EXAMPLE 545 Synthesis of4-cyano-N-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methyl-benzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

White Solid

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.31 (br, 2H), 2.91(s, 3H), 3.21-3.40 (m, 4H), 3.30 (s, 3H), 3.50-3.75 (m, 1H), 3.93 (br,2H), 4.00-4.13 (m, 3H), 4.69 (br, 2H), 6.87-6.92 (m, 2H), 7.39 (d, J=9.0Hz, 1H), 7.71 (d, J=7.8 Hz, 2H), 7.92 (d, J=7.8 Hz, 1H), 8.28 (br, 2H),8.94 (br, 2H).

EXAMPLE 546 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methyl-2-thiophen-2-ylacetamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

White Solid

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.26 (br, 2H), 3.08(s, 3H), 3.22 (br, 2H), 3.31 (s, 3H), 3.45-3.63 (m, 3H), 3.67-3.86 (m,2H), 3.97 (s, 2H), 3.98-4.10 (m, 3H), 4.62 (br, 2H), 6.87-6.97 (m, 4H),7.36-7.39 (m, 2H), 8.20 (br, 2H), 8.90 (br, 2H).

EXAMPLE 547 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methyl-2-thiophen-3-ylacetamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

White Solid

¹-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.25 (br, 2H), 3.05(s, 3H), 3.22 (br, 2H), 3.31 (s, 3H), 3.49-3.80 (m, 7H), 3.95-4.10 (m,3H), 4.62 (br, 2H), 6.86-6.92 (m, 2H), 6.99-7.01 (m, 1H), 7.25 (br, 1H),7.40 (d, J=9.0 Hz, 1H), 7.44-7.46 (m, 1H), 8.21 (br, 2H), 8.91 (br, 2H).

EXAMPLE 548 Synthesis of thiazole-4-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide trihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

White Solid

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.31 (br, 2H), 3.17(s, 3H), 3.23-3.40 (m, 2H), 3.31 (s, 3H), 3.61-3.80 (m, 3H), 3.95-4.11(m, 5H), 4.66 (br, 2H), 6.89-6.92 (m, 2H), 7.40 (d, J=9.0 Hz, 1H),8.23-8.32 (m, 3H), 8.96 (br, 2H), 9.15-9.17 (m, 1H).

EXAMPLE 549 Synthesis of isoxazole-5-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamide trichloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

White Solid

¹-H NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.29 (br, 2H), 3.17(s, 3H), 3.25 (br, 2H), 3.31 (s, 3H), 3.55-3.77 (m, 3H), 3.81-4.10 (m,5H), 4.69 (br, 2H), 6.87-6.93 (m, 2H), 7.04 (d, J=1.8 Hz, 1H), 7.40 (d,J=9.0 Hz, 1H), 8.30 (br, 2H), 8.75-8.76 (m, 1H), 8.95 (br, 2H).

EXAMPLE 550 Synthesis of 5-methyl-isoxazole-3-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethyl-amino}ethyl)methylamidetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

White Solid

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.27 (br, 2H), 2.46(s, 3H), 3.11 (s, 3H), 3.21-3.47 (m, 2H), 3.32 (s, 3H), 3.50-3.95 (m,5H), 4.00-4.13 (m, 3H), 4.67 (br, 2H), 6.50 (s, 1H), 6.87-6.93 (m, 2H),7.40 (d, J=9.0 Hz, 1H), 8.24 (br, 2H), 8.93 (br, 2H).

EXAMPLE 551 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-3-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 118 to 119° C.

EXAMPLE 552 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-3-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.20-2.43 (2H, m),3.08-3.40 (5H, m), 3.43-4.68 (10H, m), 6.82-6.94 (4Hm), 7.41 (1H, d,J=8.9 Hz), 7.70-7.75 (2H, m), 7.92 (1H, d, J=1.9 Hz), 8.36-8.48 (1H, m),8.74-8.80 (1H, m), 8.94-9.02 (1H, m)

EXAMPLE 553 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-3-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.88-1.93 (2H, m),2.41 (3H, s), 2.70 (2H, t, J=6.8 Hz), 2.86 (2H, t, J=6.2 Hz), 3.39 (3H,s), 3.68-3.75 (3H, m), 3.86 (2H, t, J=6.1 Hz), 4.07 (2H, t, J=6.1 Hz)4.14-4.21 (1H, m), 6.36 (1H, d, J=7.3 Hz), 6.52 (1H, s), 6.62 (1H, s),6.67 (1H, dd, J=9.0, 2.8 Hz), 7.00 (1H, d, J=7.4 Hz), 7.07 (1H, dd,J=7.7, 4.9 Hz), 7.17 (1H, d, J=9.0 Hz), 7.50 (1H, d, J=7.8 Hz), 8.42(1H, d, J=4.8 Hz), 8.48 (1H, s)

EXAMPLE 554

Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo-2H-quinolin-1-yl)ethyl]pyridin-3-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.74 (3H, s), 1.00 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.18-2.39 (2H, m),3.04-3.79 (7H, m), 3.99-4.28 (3H, m), 4.42-4.94 (5H, m), 6.66 (1H, d,J=9.5 Hz), 6.78-6.97 (2H, m), 7.32 (1H, t, J=7.4 Hz), 7.40 (1H, d, J=8.9Hz), 7.63 (1H, t, J=7.2 Hz), 7.70-7.84 (3H, m), 8.00 (1H, d, J=9.5 Hz),8.39-8.52 (1H, m), 8.73-8.82 (1H, m), 8.99 (1H, s)

EXAMPLE 555 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-3-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.00 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.15-2.40 (2H, m),2.57 (2H, t, J=8.2 Hz), 2.89 (2H, t, J=7.7 Hz), 3.08-3.96 (8H, m),3.99-4.22 (3H, m), 4.29-4.51 (2H, m), 4.51-4.80 (2H, m), 6.86-6.94 (2H,m), 7.00-7.06 (1H, m), 7.20-7.32 (3H, m), 7.41 (1H, d, J=8.9 Hz),7.72-7.85 (1H, m), 8.46-8.60 (1H, m), 8.79-8.84 (1H, m), 9.04 (1H, s)

EXAMPLE 556 Synthesis of7-(3-{[2-(7-bromo-1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

Pale Yellow Powder

Melting Point 146 to 147° C.

EXAMPLE 557 Synthesis of1-ethyl-7-(3-{(2-hydroxy-pyridin-4-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 160.5 to 161.5° C.

EXAMPLE 558 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-methylpyridin-4-ylmethyl)-(2-pyridin-3-yl-ethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.74 (3H, s), 1.00 (3H, t, J=7.0 Hz), 1.31 (3H, s), 1.68-2.48(2H,m),2.64 (3H, s), 2.70-4.25 (6H, m), 3.30 (3H, s), 3.43 (2H, t, J=7.0 Hz),3.66(1H, dq, J=7.0, 7.0 Hz), 4.05 (1H, dq, J=7.0, 7.0 Hz), 4.23-4.99(2H, bs), 6.80-7.00(2H, m), 7.40(1H, d, J=9.0 Hz), 7.48-8.23(3H, m),8.32(1H, bs), 8.50-9.00(1H, m), 8.74(1H, d, J=5.7 Hz), 8.80(1H, s),12.00(1H, bs)

EXAMPLE 559 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methyl-4-trifluoromethyl-benzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

Colorless Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.30 (br, 2H), 2.91(s, 3H), 3.11-3.30 (m, 2H), 3.29 (s, 3H), 3.59-3.69 (m, 3H), 4.12 (br,2H), 4.01-4.15 (m, 3H), 4.63 (br, 2H), 6.82-6.90 (m, 2H), 7.39 (d, J=8.9Hz, 1H), 7.55-8.02 (m, 6H), 8.81 (br, 2H).

EXAMPLE 560 Synthesis of3-cyano-N-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylbenzamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

Colorless Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.32 (br, 2H), 2.92(s, 3H), 3.15-3.28 (m, 2H), 3.29 (s, 3H), 3.55-3.70 (m, 3H), 3.87 (br,2H), 4.00-4.12 (m, 3H), 4.58 (br, 2H), 6.86-6.90 (m, 2H), 7.39 (d, J=8.9Hz, 1H), 7.63-7.68 (m, 1H), 7.73-8.14 (m, 5H), 8.84 (br, 2H)

EXAMPLE 561 Synthesis of 1H-indazole-3-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamidetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

Colorless Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.73 (s, 3H), 0.99 (t, J=7.0 Hz, 3H), 1.31 (s, 3H), 2.32 (br, 2H), 3.06(br, 3H), 3.28 (br, 3H), 3.43 (br, 2H), 3.61-3.69 (m, 3H), 4.01-4.11 (m,5H), 4.67 (br, 2H), 6.84-6.89 (m, 2H), 7.20-7.24 (m, 1H), 7.33-7.36 (m,1H), 7.40-7.44 (m, 1H), 7.61-7.63 (m, 1H), 8.04 (br, 3H), 8.83 (br, 2H),13.7 (br, 1H).

EXAMPLE 562 Synthesis of 1H-pyrrole-3-carboxylicacid(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)methylamidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

Colorless Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.26 (br, 2H),3.10-3.25 (m, 5H), 3.31 (s, 3H), 3.57-3.69 (m, 3H), 3.87 (br, 2H),4.02-4.08 (m, 3H), 4.60 (br, 2H), 6.15 (s, 1H), 6.63 (br, 1H), 6.83-6.94(m, 3H), 7.39 (d, J=8.9 Hz, 1H), 7.99 (br, 2H), 8.81 (br, 2H).

EXAMPLE 563 Synthesis ofN-(2-{[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)-N-methylnicotinamidetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 487, the object compound was synthesized.

Colorless Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.33 (br, 2H), 2.98(s, 3H), 3.30 (s, 3H), 3.43 (br, 2H), 3.53-3.70 (m, 3H), 3.93-4.20 (m,5H), 4.84 (br, 2H), 6.87-6.92 (m, 2H), 7.40 (d, J=8.9 Hz, 1H), 7.78 (br,1H), 8.28 (br, 3H), 8.80 (br, 1H), 8.94 (br, 3H).

EXAMPLE 564 Synthesis of1-ethyl-7-(3-{(2-hydroxypyridin-4-ylmethyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 155 to 156° C.

EXAMPLE 565 Synthesis of1,3,3,5-Tetramethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

Colorless Solid

Melting Point 149 to 153° C.

¹H-NMR (DMSO-d₆) δppm:

0.76 (3H, s), 1.32 (3H, s), 1.73-2.42 (2H, m), 3.30 (3H, s), 3.32 (3H,s), 2.80-3.50 (4H, m), 3.83-4.81 (6H, m), 6.65-6.90 (3H, m), 6.94 (1H,d, J=1.6 Hz), 7.35 (1H, d, J=8.9 Hz), 7.71 (1H, d, J=7.5 Hz), 7.91 (1H,d, J=2.1 Hz), 7.95-8.35 (2H, m), 8.60-9.03 (2H, m).

EXAMPLE 566 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyrimidin-5-ylmethyl-amino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 154° C.

EXAMPLE 567 Synthesis of1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 128 to 129° C.

EXAMPLE 568 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]pyridin-3-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

Ivory White Powder

Melting Point 114° C.

EXAMPLE 569 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(3-methylpyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.02 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.78-2.08 (2H, m),2.27-2.46 (5H, m), 2.60-3.07 (3H, m), 3.31 (3H, s), 3.62-3.77 (2H, m),3.79-5.39 (8H, m), 6.39-6.58 (1H, m), 6.58-6.74 (1H, m), 6.80-6.90 (2H,m), 7.39 (1H, d, J=9.0 Hz), 7.45-7.59 (1H, m),7.61-7.95 (1H, m),8.30-8.61 (1H, m), 8.64-8.81 (1H, m)

EXAMPLE 570 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-methylpyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.33 (3H, s), 2.03-2.38 (2H, m),2.39 (3H, s), 2.55-2.78 (3H, m), 3.00-3.54 (5H, m), 3.62-3.71 (1H, m),3.89-4.18 (5H, m), 4.26-4.64 (4H, m), 6.55 (1H, s), 6.67-6.76 (1H, m),6.77-6.93 (2H, m), 7.39 (1H, d, J=9.0 Hz), 7.58-7.64 (1H, m) 7.79-8.25(2H, m), 8.60-8.78 (1H, m)

EXAMPLE 571 Synthesis of7-(3-{(5-chloro-pyridin-2-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-amino}-propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.20-2.32 (2H, m),2.40 (3H, s), 3.31 (3H, s) 3.37-3.46 (2H, m), 3.49-3.58 (2H, m),3.60-3.71 (1H, m), 3.99-4.69 (7H, m), 6.56 (1H, s), 6.78 (1H, d, J=7.4Hz), 6.86-6.90 (2H, m), 7.38-7.43 (1H, m), 7.64 (1H, d, J=7.3 Hz),7.68-7.73 (1H, m) 8.04-8.09 (1H, m), 8.54 (1H, s)

EXAMPLE 572 Synthesis of1-ethyl-7-(3-{(6-methoxy-pyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}-propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 114 to 116° C.

EXAMPLE 573 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(4-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 147 to 148° C.

EXAMPLE 574 Synthesis of1-ethyl-7-(3-{(6-methoxy-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 111 to 113° C.

EXAMPLE 575 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 111 to 114° C.

EXAMPLE 576 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-2-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Solid

Melting Point 94.6 to 95.4° C.

EXAMPLE 577 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-yl-ethyl)-quinolin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

Melting Point 139 to 143° C.

EXAMPLE 578 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(4-methylpyridin-3-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 123 to 124° C.

EXAMPLE 579 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-pyridin-3-yl-ethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (D₂O) δppm:

0.64 (3H, s), 0.96 (3H, t, J=7.0 Hz), 1.29(3H, s), 2.21(2H, quin, J=2.8Hz), 3.25(3H, s), 3.27-3.35 (2H, m), 3.55 (2H, t, J=7.0 Hz), 3.57-3.69(3H, m), 3.71 (2H, t, J=5.4 Hz), 4.02 (1H, dq, J=7.0, 7.0 Hz), 4.12 (2H,t, J=5.4 Hz), 4.38-4.53 (2H,m), 6.75(1H, s), 6.81-6.93(3H, m), 7.33(1H,d, J=9.0 Hz), 7.50(1H, d, 7.5 Hz), 7.58-7.65(1H, m), 7.77-7.90(1H, m),8.30-8.40(1H, m), 8.57(1H, d, J=5.6 Hz), 8.61(1H, s)

EXAMPLE 580 Synthesis of1-ethyl-7-(3-{(4-methoxy-benzyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionehydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

Melting Point 116.3 to 120° C. (dec.)

EXAMPLE 581 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(6-methylpyridin-3-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 120 to 122° C.

EXAMPLE 582 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(6-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 136 to 138° C.

EXAMPLE 583 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(6-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.86-1.95 (2H, m),2.48 (3H, s), 2.70 (2H, t, J=6.8 Hz), 2.85 (2H, t, J=6.2 Hz), 3.39 (3H,s), 3.63 (2H, s), 3.65-3.75 (1H, m), 3.86 (2H, t, J=6.1 Hz), 4.06 (2H,t, J=6.1 Hz), 4.14-4.22 (1H, m), 6.41 (1H, dd, J=7.4, 0.8 Hz), 6.62 (1H,d, J=2.7 Hz), 6.67 (1H, dd, J=9.0, 2.4 Hz), 6.90-6.95 (2H, m), 7.07 (1H,d, J=7.4 Hz), 7.18 (1H, d, J=8.9 Hz), 7.35-7.42 (1H m), 7.47 (1H, d,J=2.1 Hz), 8.31 (1H, d, J=1.8 Hz))

EXAMPLE 584 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-yl-ethyl)-quinolin-5-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

Pale Yellow White Amorphous

¹H-NMR (D₂O) δppm:

0.66 (3H, s), 0.97 (3H, t, J=7.1 Hz), 1.30(3H, s), 2.12-2.37(2H,m),3.25(3H, s), 3.36-3.57 (4H, m), 3.57-3.74 (3H, m), 3.93-4.10 (3H, m),5.08 (2H, s), 6.69(1H, dd, J=9.0 and 2.8 Hz), 6.71(1H, d, J=2.8 Hz),7.30(1H, d, J=9.0 Hz), 7.93(1H, dd, J=8.0 and 5.8 Hz), 7.98-8.13(3H, m),8.23(1H, d, J=8.3 Hz), 8.43(1H, d, J=8.3 Hz), 8.63(1H, d, J=5.7 Hz),8.67(1H, s), 9.04-9.13(1H, m); 9.23(1H, d, J=8.7 Hz)

EXAMPLE 585 Synthesis of5-Ethyl-1,3,3-trimethyl-7-(3-{[2-(1-oxo-5,6,7,8-tetrahydro-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.49-1.74 (4H, m),2.03-2.40 (4H,m), 2.90-3.41(4H, m), 3.32 (3H, s), 3.56-4.84 (10H, m),6.02 (1H, d, J=6.8 Hz), 6.79-7.00 (2H, m), 7.31-7.57 (2H, m), 7.93-8.25(2H, m), 8.68-9.08 (2H, m).

EXAMPLE 586 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(2-methyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 96 to 99° C.

EXAMPLE 587 Synthesis of7-{3-[benzothiazol-2-ylmethyl-(2-pyridin-3-yl-ethyl)amino]propoxy}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (D₂O) δppm:

0.60 (3H, s), 0.95 (3H, t, J=7.1 Hz), 1.28(3H, s), 2.06-2.37(2H,m),3.07(3H, s), 3.34-3.43 (2H, m), 3.47-3.56 (2H, m), 3.59 (1H, dq, J=7.0,7.0 Hz), 3.63-3.73 (2H,m), 3.98 (1H, dq, J=7.0, 7.0 Hz), 4.03-4.16(2H,m), 4.85 (1H, d, J=15.2 Hz), 4.89 (1H, d, J=15.2 Hz), 6.51(1H, d,J=2.8 Hz), 6.71(1H, dd, J=9.1 and 2.8 Hz), 7.20(1H, d, J=9.1 Hz),7.38-7.53(2H,m), 7.83(1H, d, J=8.0 Hz), 7.87(1H, dd, J=8.0 and 5.8 Hz),7.91(1H, d, J=8.0 Hz), 8.43(1H, d, J=8.0 Hz), 8.56(1H, d, J=5.8 Hz),8.66(1H, s)

EXAMPLE 588 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(5-methylpyridin-3-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 130 to 131° C.

EXAMPLE 589 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(5-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 125 to 127° C.

EXAMPLE 590 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(4-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.0 Hz), 1.53 (3H, s), 1.91-2.01 (2H, m),2.25 (3H, s), 2.76 (2H, t, J=6.8 Hz), 2.87 (2H, t, J=6.5 Hz), 3.39 (3H,s), 3.65-3.74 (3H, m), 3.91 (2H, t, J=6.2 Hz), 4.02 (2H, t, J=6.4 Hz)4.11-4.22 (1H, m), 6.41 (1H, d, J=7.3 Hz), 6.65 (1H, d, J=2.6 Hz), 6.70(1H, dd, J=8.9, 2.7 Hz), 6.91-6.97 (3H, m), 7.17 (1H, d, J=9.0 Hz), 7.47(1H, d, J=2.0 Hz), 8.32 (1H, d, J=4.8 Hz), 8.40 (1H, s)

EXAMPLE 591 Synthesis of¹-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 115 to 117° C.

EXAMPLE 592 Synthesis of7-{3-[(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (D₂O) δppm:

0.70 (3H, s), 0.97 (3H, t, J=7.0 Hz), 1.30(3H, s), 2.06(3H, s),2.13-2.30(2H,m),3.29 (3H, s), 3.30-3.37 (2H, m), 3.37-3.48 (2H, m),3.48-3.68 (3H, m), 3.73 (3H, s), 4.03 (1H, dq, J=7.0, 7.0 Hz), 4.09 (2H,t, J=5.4 Hz), 4.53 (2H, s), 6.30(1H, s), 6.84(1H, d, J=2.7 Hz), 6.87(1H,dd, J=9.0 and 2.7 Hz), 7.36(1H, d, J=9.0 Hz), 7.95(1H, dd, J=8.0 and 5.9Hz)), 8.44(1H, d, J=8.0 Hz), 8.64(1H, d, J=5.9 Hz), 8.66(1H, s)

EXAMPLE 593 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-thiazol-5-ylmethyl)-(2-pyridin-3-yl-ethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

Melting Point 175 to 185° C.

EXAMPLE 594 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(5-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 128 to 129° C.

EXAMPLE 595 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 95 to 98° C.

EXAMPLE 596 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-methyl-2H-pyrazol-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 119 to 121° C.

EXAMPLE 597 Synthesis of7-(3-{(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.2 Hz), 1.32 (3H, s), 2.22-2.38 (5H, m),3.20-3.41 (5H, m), 3.41-3.49 (2H, m), 3.72 (3H, s), 4.04-4.17 (1H, m),4.26-4.38 (2H, m), 4.40-4.47 (2H, m), 6.74 (1H, d, J=7.4 Hz), 6.88-6.95(2H, m), 7.42 (1H, d, J=8.9 Hz), 7.51-7.56 (2H, m), 7.62 (1H, s),7.66-7.78 (2H, m), 8.24 (1H, d, J=8.0 Hz)

EXAMPLE 598 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(6-methylpyridin-3-ylmethyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 140 to 142° C.

EXAMPLE 599 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(6-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 126 to 129° C.

EXAMPLE 600 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(6-methylpyridin-3-ylmethyl)-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 120 to 122° C.

EXAMPLE 601 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(1-oxo-1H-isoguinolin-2-yl)ethyl]amino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 98 to 102° C.

EXAMPLE 602 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]thiazol-2-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 175 to 176° C.

EXAMPLE 603 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]oxazol-2-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 130 to 131° C.

EXAMPLE 604 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]thiazol-5-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 181 to 183° C.

EXAMPLE 605 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]oxazol-5-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.0 Hz), 1.53 (3H, s), 1.83-1.90 (2H, m),2.40 (3H, s), 2.65-2.75 (2H, m), 2.83-2.92 (2H, m), 3.40 (3H, s),3.65-3.72 (1H, m), 3.79 (2H, s), 3.82-3.88 (2H, m) 4.03-4.08 (2H, m),4.10-4.22 (1H, m), 6.35 (1H, d, J=7.3 Hz), 6.54 (1H, s), 6.63-6.73 (2H,m), 6.92 (1H, s), 7.09 (1H, d, J=7.4 Hz), 7.18 (1H, d, J=8.9 Hz), 7.74(1H, s)

EXAMPLE 606 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]thiazol-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 136 to 137° C.

EXAMPLE 607 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]oxazol-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 119 to 120° C.

EXAMPLE 608 Synthesis of1-ethyl-7-(3-{(2-ethylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.15-1.31 (3H, m), 1.33 (3H, s),1.75-2.41 (2H,m), 2.93-3.26 (3H, m), 3.31 (3H, s), 3.54-4.93 (11H, m),6.58-7.03 (4H, m), 7.39 (1H, d, J=8.9 Hz), 7.46-7.85 (2H, m), 7.90 (1H,s), 8.42-8.92 (2H, m)

EXAMPLE 609 Synthesis of1-ethyl-7-(3-{(2-ethylpyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}-propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.15-1.31 (3H, m), 1.32 (3H, s),1.82-2.00 (2H,m), 2.39 (3H, s), 2.63-2.92 (2H,m), 2.93-3.20 (2H, m),3.31 (3H, s), 3.51-4.88 (10H, m), 6.38-6.53 (2H, m), 6.54-6.92 (2H, m),7.39 (1H, d, J=9.0 Hz), 7.40-7.77 (2H, m), 8.09-8.80 (2H, m)

EXAMPLE 610 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-propylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 0.90 (3H, t, J=6.7 Hz), 1.02 (3H, t, J=7.0 Hz), 1.33 (3H,s), 1.51-1.72 (2H,m), 1.73-2.00 (2H, m), 2.61-3.12 (4H,m), 3.31 (3H, s),3.33-4.10 (10H, m), 6.55-7.03 (4H, m), 7.39 (1H, d, J=9.0 Hz), 7.43-7.68(2H, m), 7.85-7.95 (1H, m), 8.10-8.78 (2H, m)

EXAMPLE 611 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-propylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 0.91 (3H, t, J=7.1 Hz), 1.02 (3H, t, J=7.0 Hz), 1.33 (3H,s), 1.55-1.76 (2H, m), 2.39 (3H, s), 2.51-2.88 (2H, m), 2.90-3.19 (2H,m), 3.31 (3H, s), 3.55-4.81 (12H, m), 6.42-6.70 (2H, m), 6.78-6.92 (2H,m), 7.39 (1H, d, J=8.9 Hz), 7.43-7.88 (2H, m), 7.92-8.89 (2H, m)

EXAMPLE 612 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-yl-ethyl)thiazol-5-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Powder

Melting Point 163 to 166° C.

EXAMPLE 613 Synthesis of7-{3-[(2,5-dimethyl-oxazol-4-ylmethyl)-(2-pyridin-3-yl-ethyl)amino]propoxy}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (3H, s), 0.99 (3H, t, J=7.0 Hz), 1.31 (3H, s), 2.20-2.30(2H,m),2.36 (3H, s), 2.38 (3H, s), 2.70-3.85 (6H, m), 3.31 (3H, s), 3.66(1H,dq, J=7.0, 7.0 Hz), 4.05 (1H, dq, J=7.0, 7.0 Hz), 4.12 (2H, t, J=6.0Hz), 4.33 (2H, bs), 6.92(1H, dd, J=8.9 and 2.8 Hz), 6.94(1H, d, J=2.8Hz), 7.42(1H, d, J=8.9 Hz), 7.71(1H, bs), 8.13(1H, bs), 8.61-8.70(1H,m), 8.72(1H, s), 10.60(1H, bs)

EXAMPLE 614 Synthesis ofN-(2-{[[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-yl-ethyl)amino]methyl}phenyl)methanesulfon-amidedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.73 (3H, s), 0.99 (3H, t, J=7.0 Hz), 1.30 (3H, s), 2.2-2.35(2H,m), 3.04(3H, s), 3.05-3.95 (6H, m), 3.30 (3H, s), 3.65 (1H, dq, J=7.0, 7.0 Hz),4.04 (1H, dq, J=7.0, 7.0 Hz), 4.04-4.20 (2H, m), 4.59 (2H, bs),6.82-6.95 (2H, m), 7.33-7.50(3H, m), 7.50-7.60(1H, m), 7.60-7.75(1H,m),7.84 (1H, d, J=6.8 Hz), 7.96-8.16 (1H, m), 8.57-8.70 (1H, m), 8.68(1H, bs)), 10.37(1H, bs)

EXAMPLE 615 Synthesis of1-ethyl-3,3,5-trimethyl-7-(4-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-amino}butoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.62-2.14 (4H, m),2.39 (3H, s), 2.50-2.53 (3H,m), 2.73-3.08 (4H, m), 3.14-4.85 (11H, m),6.70-6.85 (1H, m), 6.86-7.02 (3H, m), 7.40 (1H, d, J=8.9 Hz), 7.67-7.99(3H, m), 8.51-9.03 (2H, m)

EXAMPLE 616 Synthesis of1-ethyl-3,3,5-trimethyl-7-{4-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-methylpyridin-3-ylmethyl)amino]butoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.53-2.15 (4H, m),2.39 (3H, s), 2.42-2.96 (7H, m), 3.26-4.88 (11H, m), 6.41-6.63 (1H, m),6.65-6.84 (1H, m), 6.87-6.95 (2H, m), 7.40 (1H, d, J=8.8 Hz), 7.52-7.89(2H, m), 8.46-8.88 (2H, m)

EXAMPLE 617 Synthesis of1-ethyl-3,3,5-trimethyl-7-(4-{(2-methylpyridin-3-ylmethyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}-butoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.60-2.14 (4H, m),2.47-3.08 (7H,m), 3.16-4.77 (11H,m), 6.58-6.80 (1H,m), 6.83-7.00 (2H,m), 7.39 (1H, d, J=8.9 Hz), 7.43-7.62 (2H, m), 7.63-7.99 (3H, m),8.12-8.30 (1H, m), 8.55-9.02 (2H, m)

EXAMPLE 618 Synthesis of1-ethyl-3,3,5-trimethyl-7-(4-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}-butoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.42-1.91 (4H, m),3.31 (3H, s), 3.33-4.71 (12H, m), 6.63-6.98 (4H, m), 7.39 (1H, d, J=8.7Hz), 7.61-7.70 (1H, m), 7.77-7.94 (3H, m), 8.66-8.82 (2H, m)

EXAMPLE 619 Synthesis of1-ethyl-3,3,5-trimethyl-7-(4-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}butoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.31 (3H, s), 1.57-1.99 (4H, m),2.49 (3H, s), 3.08-4.62 (15H, s), 6.53-6.58 (1H, m),6.69-6.76 (1H, m),6.86-6.94 (2H, m), 7.39 (1H, d, J=8.8 Hz), 7.58-7.65 (1H, m), 7.83-8.13(2H, m), 8.72-8.89 (2H, m)

EXAMPLE 620 Synthesis of1-ethyl-3,3,5-trimethyl-7-(4-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}butoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.60-1.99 (4H, m),3.07-4.70 (15H, m), 6.69 (1H, d, J=7.3 Hz), 6.83-6.98 (2H, m), 7.39 (1H,d, J=8.8 Hz) 7.48-7.55 (2H, m), 7.65-7.76 (2H,m), 7.82-8.12 (2H, m),8.20 (1H, d, J=7.9 Hz), 8.70-8.93 (2H, m)

EXAMPLE 621 Synthesis of7-(3-{(2-chloro-pyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}-propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.08-2.33 (2H, m),2.39 (3H, s), 3.17-4.85 (15H, m), 6.57 (1H, s), 6.70-6.94 (3H, m), 7.40(1H, d, J=9.0 Hz) 7.42-7.74 (2H, m), 8.21-8.57 (2H, m)

EXAMPLE 622 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

¹H-NMR (CDCl₃) δppm:

0.87 (s, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.81-1.94 (m, 2H),2.56 (s, 3H), 2.72 (t, J=6.2 Hz, 2H), 2.83-2.90 (m, 2H), 3.38 (s, 3H),3.67 (s, 2H), 3.66-3.78 (m, 1H), 3.88 (t, J=6.1 Hz, 2H), 4.08-4.23 (m,3H), 6.48 (d, J=7.1 Hz, 1H), 6.53-6.62 (m, 3H), 6.96 (d, J=7.1 Hz, 1H),7.07-7.08 (m, 2H), 7.19 (d, J=8.9 Hz, 1H), 8.28-8.32 (m, 2H).

EXAMPLE 623 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(3-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.08 (br, 2H), 2.22(s, 3H), 3.20-3.40 (m, 2H), 3.30 (s, 3H), 3.53-3.70 (m, 3H), 3.89-4.13(m, 5H), 4.24 (br, 2H), 6.67 (br, 1H), 6.70-6.83 (m, 2H), 7.38 (d, J=9.0Hz, 1H), 7.62 (br, 2H), 7.89 (br, 2H), 8.71 (br, 2H).

EXAMPLE 624 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-methyl-7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.10 (br, 2H), 2.17(s, 3H), 3.20-3.39 (m, 2H), 3.30 (s, 3H), 3.61-3.72 (m, 3H), 3.83-4.11(m, 5H), 4.16 (br, 2H), 6.77 (br, 1H), 6.85 (br, 1H), 6.96 (s, 1H), 7.31(br, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.80 (br, 2H), 8.14 (s, 1H), 8.68 (br,2H).

EXAMPLE 625 Synthesis of7-(3-{(2-butylpyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-D₆) δppm:

0.76 (3H, s), 0.86 (3H, t, J=7.3 Hz), 1.02 (3H, t, J=7.0 Hz), 1.21-1.40(5H, m), 1.47-1.67 (2H, m), 1.83-2.06 (2H, m), 2.39 (3H, s), 2.60-3.01(6H, m), 3.17 (3H, s), 3.22-4.19 (8H, m) 6.35-6.67 (2H, m), 6.69-6.92(2H, m), 7.39 (1H, d, J=8.9 Hz) 7.42-7.71 (2H, m), 8.17-8.42 (1H, m),8.53-8.65 (1H, m)

EXAMPLE 626 Synthesis of7-{3-[(2,4-dimethyl-thiazol-5-ylmethyl)-(2-pyridin-3-yl-ethyl)amino]propoxy}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹-NMR (DMSO-d₆) δppm:

0.74 (3H, s), 0.99 (3H, t, J=7.0 Hz), 1.31 (3H, s), 2.26(2H,bs), 2.39(3H, s), 2.59 (3H, s), 3.11-3.61 (6H, m), 3.31 (3H, s), 3.67(1H, t, dq=7.0, 7.0 Hz), 4.05 (1H, dq, J=7.0, 7.0 Hz), 4.09-4.17 (2H, m), 4.62(2H, bs), 6.84-6.95 (2H, m), 7.41(1H, d, J=8.9 Hz), 7.89(1H, dd, J=7.8and 5.6 Hz), 8.35(1H, d, J=7.8 Hz), 8.76 (1H, d, J=5.6 Hz), 8.84 (1H,s), 11.2 (1H, bs)

EXAMPLE 627 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridazin-4-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.87-1.97 (2H, m),2.73 (2H, t, J=6.8 Hz), 2.87-2.95 (2H, m), 3.39 (3H, s), 3.66-3.77 (3H,m), 3.85 (2H, t, J=5.9 Hz), 4.10-4.24 (3H, m), 6.48 (1H, d, J=7.4 Hz),6.59 (1H, d, J=2.7 Hz), 6.65 (1H, dd, J=2.7 and 9.0 Hz), 6.95 (1H, t,J=0.8 Hz), 7.09 (1H, d, J=7.4 Hz), 7.19 (1H, d, J=9.0 Hz), 7.25-7.28(1H, m), 7.51 (1H, d, J=2.1 Hz), 8.89 (1H, dd, J=1.2 and 5.2 Hz), 9.08(1H, s)

EXAMPLE 628 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamidehydrochloride

Using an appropriate starting material and following the procedure ofExample 4 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.74 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.85-1.97(2H, m),3.03(2H, t, J=7.0 Hz), 3.03-3.62 (4H, m), 3.31 (3H, s), 3.67 (1H, dq,J=7.0, 7.0 Hz), 3.98 (2H, t, t =7.0 Hz), 4.06 (1H, dq, J=7.0, 7.0 Hz),6.84-6.95 (2H, m), 7.41(1H, d, J=8.9 Hz), 7.54-7.63(2H, m),7.63-7.72(1H, m), 7.75-7.84(2H, m), 7.84-7.92(1H, m), 8.34(1H, d, J=7.4Hz), 8.74 (1H, d, J=5.2 Hz), 8.78 (1H, bs)

EXAMPLE 629 Synthesis of7-(3-{(2,6-dimethylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.99-3.04 (12H, m),3.05-4.82 (11H, m), 6.55-7.04 (4H, m), 7.41 (1H, d, J=8.9 Hz) 7.44-7.82(2H, m), 7.91 (1H, s), 8.38-8.92 (1H, m)

EXAMPLE 630 Synthesis of7-(3-{(2,6-dimethylpyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}-propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

White Powder

Melting Point 114 to 116° C.

EXAMPLE 631 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofExample 4, the object compound was synthesized.

White Powder

Melting Point 179.6 to 182.5° C.

EXAMPLE 632 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.00 (br, 2H), 2.16(s, 3H), 3.21-3.35 (m, 2H), 3.30 (s, 3H), 3.53-3.70 (m, 3H), 3.93 (br,4H), 4.00-4.19 (m, 3H), 6.70-6.81 (m, 2H), 6.95 (s, 1H), 7.17 (d, J=9.0Hz, 1H), 7.45 (br, 1H), 7.78 (br, 2H), 7.93 (br, 1H), 8.67 (br, 2H).

EXAMPLE 633 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzamidehydrochloride

Benzoyl chloride (0.091 ml, 0.78 mmol) was added to an acetonitrilesolution (3 ml) of1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.39g, 0.71 mmol) and triethylamine (0.12 ml, 0.86 mmol) while coolingin an ice-bath, and the mixture was stirred at room temperatureovernight. Water was added to the reaction mixture, and extraction withethyl acetate was conducted. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue thusobtained was purified by medium pressure liquid chromatography (silicagel, ethyl acetate:isopropyl alcohol=100:0→92:8). The purified productwas concentrated under reduced pressure and the resultant residue wasdissolved in ethyl acetate (10 ml). A 1N-HCl ethanol solution (0.65 ml)was added to the solution, and concentrated under reduced pressure. Theresidue was recrystallized from ethyl acetate to thereby obtain 0.28 g(yield:54%) ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzamidehydrochloride as a white powder.

Melting Point 179 to 191° C.

EXAMPLE 634 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide

Using an appropriate starting material and following the procedure ofExample 4, the object compound was synthesized.

White Powder

Melting Point 134 to 137° C.

EXAMPLE 635 Synthesis of pyridine-3-sulfonicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amide

Using an appropriate starting material and following the procedure ofExample 4, the object compound was synthesized.

White Powder

Melting Point 160 to 164° C.

EXAMPLE 636 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethyl-amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.05 (br, 2H), 2.24(s, 3H), 3.30-3.40 (m, 2H), 3.30 (s, 3H), 3.63-3.70 (m, 3H), 3.82 (br,4H), 3.95-4.10 (m, 1H), 4.25 (br, 2H), 6.72 (br, 1H), 6.80 (br 1H),7.35-7.43 (m, 3H), 7.85 (br, 2H), 8.07-8.11 (m, 1H), 8.66 (br, 2H).

EXAMPLE 637 Synthesis of pyridine-3-sulfonicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amide

Using an appropriate starting material and following the procedure ofExample 4, the object compound was synthesized.

White Powder

Melting Point 163.3 to 166.3° C.

EXAMPLE 638 Synthesis of1-ethyl-3,3,5-trimethyl-7-(2-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-amino}ethoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7 and Example 6, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.02 (3H, t, J=7.0 Hz), 1.33 (3H, s), 2.61 (3H, s),2.77-3.05(4H, m), 3.32(3H, s), 3.48-3.71(3H, m), 3.94-4.16(5H, m),6.63(1H, d, J=7.3 Hz), 6.83-6.91 (3H,m), 7.39(1H, d, J=8.8 Hz),7.55(1H), d, J=7.6 Hz), 7.65(1H, t, J=6.2 Hz), 7.84(1H, d, J=2.1 Hz),8.34-8.38 (1H, m), 8.51(1H, d, J=5.9 Hz)

EXAMPLE 639 Synthesis of pyridine-3-sulfonicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-ylethyl)amide2 phosphate

Using an appropriate starting material and following the procedure ofExample 4 and Example 458, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.74 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.89-2.08(2H, m),2.80-2.98(2H, m), 3.31 (3H, s), 3.31-5.00 (8H, m), 6.84-6.96 (2H, m),7.30(1H, dd, J=8.0 and 4.8 Hz), 7.40(1H, d, J=8.7 Hz), 7.54-7.74(2H, m),8.18-8.27(1H, m), 8.42(1H, dd, J=4.8 and 1.5 Hz), 8.44 (1H, d, J=1.8Hz), 8.83(1H, dd, J=4.8 Hz, J=1.5 Hz), 8.99 (1H, d, J=1.8 Hz)

EXAMPLE 640 Synthesis of 2,4-dimethyl-thiazole-5-sulfonicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-yl-ethyl)amidehydrochloride

Using an appropriate starting material and following the procedure ofExample 4 and Example 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.89-2.25(2H, m),2.49 (3H, s), 2.62 (3H, s), 3.08 (2H, t, J=7.0 Hz), 3.32 (3H, s),3.32-3.90 (3H, m), 3.54 (2H, t, J=7.0 Hz), 4.01 (2H, t, J=7.0 Hz),4.01-4.20 (1H, m), 6.84-6.96 (2H, m), 7.41(1H, d, J=8.9 Hz), 7.90(1H,dd, J=8.0 and 5.4 Hz), 8.37 (1H, d, J=8.0 Hz), 8.75(1H, d, J=5.4 Hz),8.82 (1H, s)

EXAMPLE 641 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]pyridin-3-ylmethylamino}-propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 1.81-1.93 (m, 2H),2.72 (t, J=6.8 Hz, 2H), 2.89 (t, J=6.1 Hz, 2H), 3.38 (s, 3H), 3.68 (s,2H), 3.60-3.75 (m, 1H), 3.86 (t, J=6.0 Hz, 2H), 4.05-4.21 (m, 3H), 6.55(d, J=7.1 Hz, 1H), 6.60-6.68 (m, 2H), 6.96-7.03 (m, 1H), 7.07 (d, J=7.1Hz, 1H), 7.12-7.18 (m, 2H), 7.42-7.50 (m, 1H), 7.66-7.70 (m, 1H),8.35-8.37 (m, 1H), 8.47 (s, 1H).

EXAMPLE 642 Synthesis of1-ethyl-7-(3-{[2-(2-ethyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]pyridin-3-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.5 Hz, 3H), 1.32 (s,3H), 2.25 (br, 2H), 2.87 (q, J=7.5 Hz, 2H), 3.20-3.35 (m, 2H), 3.32 (s,3H), 3.51-3.69 (m, 3H), 3.97-4.15 (m, 5H), 4.28 (br, 2H), 6.90 (br, 3H),7.22 (s, 1H), 7.42 (d, J=9.0 Hz, 1H), 7.50-7.68 (m, 2H), 8.18 (br, 1H),8.73 (br, 1H), 8.80 (br, 1H).

EXAMPLE 643 Synthesis of1-ethyl-7-(3-{[2-(7-methoxy-2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-3-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.02 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.31 (br, 2H),2.51-2.60 (m, 2H), 2.77-2.82 (m, 2H), 3.28 (br, 2H), 3.32 (s, 3H),3.50-3.70 (m, 3H), 3.77 (s, 3H), 4.01-4.14 (m, 3H), 4.43 (br, 2H), 4.68(br, 2H), 6.60 (dd, J=2.0, 8.2 Hz, 1H), 6.79 (br, 1H), 6.91 (dd, J=2.8,9.0 Hz, 1H), 6.94 (d, J=2.8 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.41 (d,J=9.0 Hz, 1H), 7.90 (br, 1H), 8.67 (br, 1H), 8.87 (br, 1H), 9.12 (br,1H).

EXAMPLE 644 Synthesis of 2,4-dimethyl-thiazole-5-sulfonicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amide

Using an appropriate starting material and following the procedure ofExample 4, the object compound was synthesized.

White Powder

Melting Point 76 to 84° C.

EXAMPLE 645 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-2-trifluoromethyl-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.02 (t, J=7.0 Hz, 3H), 1.32 (t, J=7.5 Hz, 3H), 2.45-2.60(m, 2H), 3.20-3.35 (m, 2H), 3.30 (s, 3H), 3.59-3.70 (m, 3H), 3.81 (br,4H), 3.98-4.06 (m, 1H), 4.13 (br, 2H), 6.63-6.80 (m, 3H), 7.36 (d, J=9.0Hz, 1H), 7.61-7.87 (m, 4H), 8.65 (br, 2H).

EXAMPLE 646 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-2-trifluoromethyl-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.02 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 1.98 (br, 2H), 2.74(br, 5H), 3.20-3.35 (m, 2H), 3.31 (s, 3H), 3.55-3.69 (m, 3H), 3.99-4.10(m, 5H), 6.70-6.90 (m, 3H), 7.39 (d, J=9.0 Hz, 1H), 7.76 (br, 3H), 8.26(br, 1H), 8.59 (br, 1H).

EXAMPLE 647 Synthesis of7-(3-{(2,4-dimethylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.76 (s, 3H), 1.02 (t, J=7.0 Hz, 3H), 1.33 (s, 3H), 1.99 (br, 2H), 2.43(br, 3H), 2.62 (br, 3H), 2.73 (br, 4H), 3.33 (s, 3H), 3.61-3.70 (m, 3H),3.90-4.10 (m, 5H), 6.59 (br, 1H), 6.82-6.92 (m, 3H), 7.40 (d, J=9.0 Hz,1H), 7.49 (br, 2H), 7.87 (br, 1H), 8.40 (br, 1H).

EXAMPLE 648 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-trifluoromethylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.85-1.94 (m, 2H),2.78 (t, J=7.2 Hz, 2H), 2.89 (t, J=6.2 Hz, 2H), 3.38 (s, 3H), 3.63-3.76(m, 1H), 3.87-3.93 (m, 4H), 4.03-4.22 (m, 3H), 6.41-6.44 (m, 1H), 6.61(d, J=2.7 Hz, 1H), 6.67 (dd, J=9.0 and 2.7 Hz, 1H), 6.94-6.95 (m, 1H),7.01-7.08 (m, 2H), 7.19 (d, J=9.0 Hz, 1H), 7.50-7.51 (m, 1H), 7.79-7.81(m, 1H), 8.46 (d, J=3.6 Hz, 1H).

EXAMPLE 649 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-trifluoromethylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (s, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.53 (s, 3H), 1.87-1.95 (m, 2H),2.43 (s, 3H), 2.78 (t, J=7.2 Hz, 2H), 2.88 (t, J=6.2 Hz, 2H), 3.38 (s,3H), 3.63-3.76 (m, 1H), 3.86 (s, 2H), 3.92 (t, J=6.0 Hz, 2H), 4.05-4.22(m, 3H), 6.34-6.37 (m, 1H), 6.53 (s, 1H), 6.63 (d, J=2.7 Hz, 1H), 6.68(dd, J=9.0 and 2.7 Hz, 1H), 6.99 (d, J=7.4 Hz, 1H), 7.01-7.09 (m, 1H),7.19 (d, J=9.0 Hz, 1H), 7.80-7.84 (m, 1H), 8.45 (d, J=3.6 Hz, 1H).

EXAMPLE 650 Synthesis of1-Ethyl-3,3,5-trimethyl-7-(3-{[3-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)propyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride dihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.76 (s, 3H), 1.02 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.22 (br, 4H), 2.39(s, 3H), 3.10 (br, 2H), 3.21 (br, 2H), 3.31 (s, 3H), 3.45-3.70 (m, 1H),4.01-4.10 (m, 5H), 4.58 (br, 2H), 6.56 (s, 1H), 6.79 (d, J=7.4 Hz, 1H),6.87-6.92 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 7.57 (d, J=7.4 Hz, 1H), 8.08(br, 2H), 8.82 (br, 2H).

EXAMPLE 651 Synthesis of pyrazine-2-carboxylicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-ylethyl)amidehydrochloride

Using an appropriate starting material and following the procedure ofExample 45, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.75 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.89-2.25(2H, m),3.00-3.23 (2H, m), 3.29 and 3.32 (3H, s), 3.32-3.78 (4H, m),3.78-3.95(2H, m), 3.95-4.29 (2H, m), 6.67-6.80 (1H, m), 6.92-7.07 (1H,m), 7.36 and 7.42(1H, d, J=9.5 Hz), 7.80 and 7.95(1H, dd, J=7.7 and 5.6Hz), 8.14 and 8.48(1H, d, J=8.0 Hz), 8.52-9.02(5H, m)

EXAMPLE 652 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2,4,6-trimethylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydro-enzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.76 (s, 3H), 1.02 (t, J=7.0 Hz, 3H), 1.33 (s, 3H), 2.00 (br, 2H), 2.36(br, 3H), 2.43-2.62 (m, 6H), 2.76 (br, 4H), 3.33 (s, 3H), 3.55-3.68 (m,3H), 3.95 (br, 2H), 4.03-4.11 (m, 3H), 6.59 (br, 1H), 6.80-6.94 (m, 3H),7.27 (br, 1H), 7.39-7.47 (m, 2H), 7.89 (s, 1H).

EXAMPLE 653 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)nicotinamide

Using an appropriate starting material and following the procedure ofExample 459, the object compound was synthesized.

White Powder

Melting Point 135.5 to 138.1° C.

EXAMPLE 654 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-pyridin-4-ylmethylnicotinamide2.5 phosphate

Using an appropriate starting material and following the procedure ofExample 633 and Example 458, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75(3H, s), 1.00 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.82-2.27(2H, m),3.29 (3H, s), 3.36-3.52 (2H, m), 3.52-4.25(4H, m), 4.57 and 4.78 (2H,s), 6.53-7.09 (2H, m), 7.09-7.56(4H, m), 7.69-8.05 (1H, m), 8.37-8.88(4H, m)

EXAMPLE 655 Synthesis of thiazole-4-carboxylicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-ylethyl)amidehydrochloride

Using an appropriate starting material and following the procedure ofExample 45, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (3H, s), 1.00 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.89-2.25(2H, m),2.87-3.21 (2H, m), 3.31 (3H, s), 3.31-4.27 (8H, m), 6.74-6.94 (1H, m),6.95-7.05 (1H,m), 7.28-7.47 (1H,m), 7.65-7.94 (1H,m), 8.01 (1H, bs),8.06-8.50 (1H, m), 8.50-8.94 (2H, m), 9.05-9.22 (1H, m)

EXAMPLE 656 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-pyridin-3-yl-N-pyridin-4-ylmethylacetamide1.5 methanesulfonate

Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) (0.3 g, 0.68 mmol) was added to a dichloromethane solution (6 ml)of1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.39 g, 0.73 mmol), 3-pyridylacetic acid hydrochloride (0.14 g, 0.8mmol), andtriethylamine (0.31 ml, 2.2 mmol) while cooling in anice-bath, and the mixture was stirred at room temperature overnight.Water was added to the reaction mixture, and extraction withdichloromethane was conducted. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue thus obtained was purified by medium pressure liquidchromatography (NH-silica gel, ethyl acetate:isopropylalcohol=100:0→91:9). The purified product was concentrated under reducedpressure and the resultant residue was dissolved in ethanol (10 ml).Methanesulfonic acid (0.047 ml, 0.72 mmol) was added to the solution,and concentrated under reduced pressure. The resultant residue waswashed with diethylether by decantation to thereby obtain 0.17 g (yield:35%) ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-pyridin-3-yl-N-pyridin-4-ylmethylacetamide1.5 methanesulfonate as a pale yellow white amorphous solid.

¹H-NMR (DMSO-D₆) δppm:

0.73 (3H, s), 1.00 (3H, t, J=7.3 Hz), 1.32 (3H, s), 1.85-2.25(2H, m),2.35 (4.5H, s), 3.29 and 3.30 (3H, s), 3.30-3.97 (2H, m), 3.97-4.27 (6H,m), 4.79 and 4.99 (2H, s), 6.82-7.04 (2H, m), 7.33-7.48 (1H, m),7.54-7.95 (3H, m), 8.10-8.23 (1H, m), 8.57-8.90(4H, m)

EXAMPLE 657 Synthesis of oxazole-4-carboxylicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-ylethyl)amidehydrochloride

Using an appropriate starting material and following the procedure ofExample 45, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.74 (3H, s), 1.00 (3H, t, J=7.3 Hz), 1.32 (3H, s), 1.98-2.25(2H, m),3.03-3.21 (2H, m), 3.31 (3H, s), 3.40-4.22 (8H, m), 6.74-7.05 (2H, m),7.31-7.47 (1H, m), 7.75-8.03 (1H, m), 8.32 (1H, d, J=7.3 Hz), 8.37-8.60(2H, m), 8.60-8.97 (2H, m)

EXAMPLE 658 Synthesis of thiophene-3-carboxylicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-ylethyl)amidehydrochloride

Using an appropriate starting material and following the procedure ofExample 633, the object compound was synthesized.

¹H-NMR (DMSO-D₆) δppm:

0.74 (3H, s), 1.00 (3H, t, J=7.2 Hz), 1.32 (3H, s), 1.88-2.25(2H, m),3.09 (2H, bs), 3.31 (3H, s), 3.32-4.30 (8H, m), 6.64-7.18 (3H, m), 7.39(1H, d, J=9.3 Hz), 7.55 (1H, dd, J=4.9 and 2.9 Hz), 7.62 (1H, bs),7.67-8.22 (1H, m), 8.22-.18 (3H, m)

EXAMPLE 659 Synthesis of furan-2-carboxylicacid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-ylethyl)amidehydrochloride

Using an appropriate starting material and following the procedure ofExample 633, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (3H, s), 1.01 (3H, t, J=7.0 Hz), 1.32 (3H, s), 1.92-2.12 (2H, m),3.01-3.21 (2H, m), 3.31 (3H, s), 3.30-3.90 (5H, m), 4.00-4.15 (3H, m),6.56-6.62 (1H, m), 6.85-7.00 (3H, m), 7.36-7.45 (1H, m), 7.78 (1H, s),7.85-8.00 (1H, m), 8.38 (1H, bs), 8.74 (1H, d, J=5.3 Hz), 8.82 (1H, bs)

EXAMPLE 660 Synthesis of1,3,3,5-tetramethyl-7-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.87 (3H, s), 1.53 (3H, s), 1.92-2.10 (2H, m), 2.84 (2H, t, J=6.8 Hz),3.39 (3H, s), 3.41 (3H, s), 3.85 (2H, s), 4.08 (2H, t, J=6.2), 6.71 (1H,d, J=2.7 Hz), 6.80 (1H, dd, J=2.7 and 9.0 Hz), 7.14 (1H, d, J=9.0),7.20-7.34 (2H, m), 8.45-8.65 (2H, m).

EXAMPLE 661 Synthesis of1-ethyl-7-{2-hydroxy-3-[2-(1-oxo-1H-isoquinolin-2-yl)ethylamino]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.84 (3H, s), 1.14 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.75-3.04 (2H, m),3.11 (2H, t, J=6.1 Hz), 3.78 (3H, s), 3.59-3.79 (1H, m), 3.89-4.29 (6H,m), 6.52 (1H, d, J=7.3 Hz), 6.68-6.86 (2H, m), 7.11 (1H, d, J=7.3 Hz),7.18 (1H, d, J=8.7 Hz), 7.43-7.57 (2H, m), 7.57-7.74 (1H, m), 8.42 (1H,d, J=8.2 Hz).

EXAMPLE 662 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.96-2.06 (2H, m),2.85 (2H, t, J=6.8 Hz), 3.39 (3H, s),3.65-3.74 (1H,m), 3.85 (2H,s), 4.07(2H, t, J=6.1 Hz), 4.10-4.21 (1H, m), 6.71 (1H, d, J=2.8 Hz), 6.80 (1H,dd, J=9.0 and 2.8 Hz), 7.19 (1H, d, J=9.0 Hz), 7.22-7.29 (1H, m),7.65-7.68 (1H, m), 8.50 (1H, d, J=1.6 Hz), 8.58-8.61 (1H, m)

EXAMPLE 663 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.92-2.00 (2H, m),2.41 (3H, s), 2.88 (2H, t, J=6.8 Hz), 3.03 (2H, t, J=6.2 Hz) 3.39 (3H,s),3.62-3.74 (1H, m), 4.02 (2H, t, J=6.1 Hz), 4.14 (2H, t, J=6.2 Hz),4.16-4.22 (1H, m), 6.42 (1H, d, J=9.0 Hz), 6.54 (1H, s), 6.70 (1H, d,J=2.7 Hz), 6.72-6.82 (1H, m), 7.13-7.20 (2H, m)

EXAMPLE 664 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-2-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.03-2.09 (2H, m),2.91 (2H, t, J=6.7 Hz), 3.48 (3H, s), 3.64-3.76 (1H, m), 3.97 (2H,s),4.10 (2H, t, J=6.2 Hz), 4.14-4.23 (1H, m), 6.73 (1H, d, J=2.7 Hz), 6.82(1H, dd, J=9.0 and 2.7 Hz), 7.16-7.21 (2H, m), 7.27-7.32 (1H, m), 7.85(1H, td, J=7.7, 1.8 Hz), 8.58-8.56 (1H, m)

EXAMPLE 665 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethylamino]propoxy}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.91-2.00 (2H, m),2.85 (2H, t, J=6.7 Hz), 3.03 (2H, t, J=6.2 Hz), 3.39 (3H, s),3.66-3.76(1H, m), 4.02 (2H, t, J=6.1 Hz), 4.09-4.24 (3H, m), 6.48 (1H, d, J=7.4Hz), 6.69 (1H, d, J=2.8 Hz), 6.76 (1H, dd, J=9.0, 2.8 Hz), 6.97 (1H, d,J=2.0 Hz), 7.16-7.24 (2H, m), 7.48 (1H, d, J=2.1 Hz)

EXAMPLE 666 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J =7.0 Hz), 1.53 (3H, s), 1.98-2.07 (2H, m),2.57 (3H, s), 2.89 (2H, t, J=6.8 Hz), 3.39 (3H, s),3.62-3.73 (1H, m),3.82 (2H,s), 4.07-4.21 (3H, m), 6.71 (1H, d, J=2.8 Hz), 6.80 (1H, dd,J=9.0 and 2.8 Hz), 7.10 (1H, dd, J =7.7 and 4.9 Hz), 7.20 (1H, d, J=9.0Hz), 7.59-7.62 (1H, m), 8.38-8.41 (1H, m)

EXAMPLE 667 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(6-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.95-2.07 (2H, m),2.54 (3H, s), 2.84 (2H, t, J=6.8 Hz), 3.39 (3H, s),3.64-3.76 (1H, m),3.80 (2H,$), 4.04-4.20 (3H, m), 6.71 (1H, d, J=2.8 Hz), 6.79 (1H, dd,J=9.0 and 2.8 Hz), 7.11 (1H, d, J=7.9 Hz), 7.19 (1H, d, J=9.0 Hz), 7.56(1H, dd, J=7.9 and 2.3 Hz), 8.44-8.45 (1H, m)

EXAMPLE 668 Synthesis of1-ethyl-7-[3-(4-methoxybenzylamino)propoxy]-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86(3H, s), 1.14 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.00 (2H, quin, J=6.5Hz), 2.83(2H, t, J=6.5H), 3.39 (3H, s), 3.70 (1H, dq, J=7.0, 7.0 Hz),3.76 (2H, s), 3.80 (3H, s), 4.07(2H, t, J=6.5 Hz), 4.18 (1H, dq, J=7.0,7.0 Hz), 6.71 (1H, d, J=2.7 Hz), 6.80 (1H, dd, J=2.7 and 9.0 Hz), 6.86(2H, d, J=8.5 Hz), 7.19 (1H, d, J=9.0 Hz), 7.24 (2H, d, J=8.5 Hz)

EXAMPLE 669 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(5-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.50 (3H, s), 1.98-2.05 (2H, m),2.32 (3H, s), 2.85 (2H, t, J=6.8 Hz), 3.39 (3H, s),3.62-3.72 (1H, m),3.81 (2H,s), 4.05-4.17 (3H, m), 6.71 (1H, s), 6.80 (1H, dd, J=9.0 and2.8 Hz), 7.19 (1H, d, J=9.0 Hz), 7.48 (1H, s), 8.34-8.38 (2H, m)

EXAMPLE 670 Synthesis of1-ethyl-7-{3-[(2-ethylpyridin-3-ylmethyl)amino]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.29 (3H, t, J=7.5 Hz), 1.52 (3H,s), 1.99-2.05 (2H, m), 2.82-2.91 (4H, m), 3.39 (3H, s),3.62-3.75 (1H,m), 3.84 (2H,s), 4.09 (2H, t, J=6.2 Hz) 4.10-4.23 (1H, m), 6.71 (1H, d,J=2.8 Hz), 6.80 (1H, dd, J=9.0 and 2.8 Hz), 7.09 (1H, dd, J=7.6 and 4.9Hz), 7.20 (1H, d, J=9.0 Hz), 7.63 (1H, d, J=7.7 Hz), 8.43-8.46 (1H, m)

EXAMPLE 671 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-propylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 0.99 (3H, t, J=7.4 Hz), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H,s), 1.69-1.81 (2H, m), 1.99-2.07 (2H, m), 2.77-2.90 (4H, m), 3.39 (3H,s), 3.60-3.73 (1H, m), 3.84 (2H,s), 4.06-4.23 (3H, m), 6.72 (1H, s),6.79 (1H, dd, J=9.0 and 2.8 Hz), 7.06-7.09 (1H, m), 7.20 (1H, d, J=8.0Hz), 7.63 (1H, d, J=7.7 Hz), 8.42-8.45 (1H, m)

EXAMPLE 672 Synthesis of1-ethyl-3,3,5-trimethyl-7-{4-[(2-methylpyridin-3-ylmethyl)amino]butoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.54 (3H, s), 1.67-1.75 (2H, m),1.85-1.92 (2H, m), 2.58 (3H, s), 2.76 (2H, t, J=7.0 Hz), 3.39 (3H, s),3.60-3.77 (1H, m), 3.80 (2H,s), 3.99 (2H, t, J=6.3 Hz), 4.11-4.22 (1H,m), 6.74 (1H, s), 6.79 (1H, dd, J=8.9 and 2.8 Hz), 7.10 (1H, dd, J=7.6and 4.9 Hz), 7.19 (1H, d, J=9.0 Hz), 7.61 (1H, d, J=6.1 Hz), 8.38-8.41(1H, m)

EXAMPLE 673 Synthesis of1-ethyl-3,3,5-trimethyl-7-{4-[(pyridin-4-ylmethyl)amino]butoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.64-1.78 (2H, m),1.83-1.95 (2H, m), 2.72 (2H, t, J=7.1 Hz), 3.39 (3H, s), 3.63-3.73 (1H,m), 3.84 (2H,s), 3.99 (2H, t, J=6.3 Hz), 4.09-4.21 (1H, m), 6.71 (1H,s), 6.79 (1H, dd, J=9.0 and 2.8 Hz), 7.19 (1H, d, J=9.0 Hz), 7.26-7.29(2H, m), 8.55 (2H, dd, J=4.4 and 1.6 Hz)

EXAMPLE 674 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(pyridazin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.97-2.06 (2H, m),2.85 (2H, t, J=6.7 Hz), 3.40 (3H, s), 3.65-3.75 (1H, m), 3.90 (2H,s),4.09 (2H, t, J=6.0 Hz), 4.10-4.22 (1H, m), 6.71 (1H, d, J=2.8 Hz), 6.80(1H, dd, J=9.0 and 2.8 Hz), 7.21 (1H, d, J=9.0 Hz), 7.46-7.49 (1H, m),9.11 (1H, dd, J=5.2 and 1.2 Hz), 9.21 (1H, s)

EXAMPLE 675 Synthesis of7-{3-[(2,6-dimethylpyridin-3-ylmethyl)amino]propoxy}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.97-2.05 (2H, m),2.50 (3H, s), 2.54 (3H, s), 2.87 (2H, t, J=6.7 Hz), 3.39 (3H, s),3.60-3.77 (1H, m), 3.78 (2H,s), 4.06-4.24 (3H, m), 6.71 (1H, s), 6.80(1H, dd, J=9.0 and 2.8 Hz), 6.95 (1H, d, J=7.3 Hz), 7.20 (1H, d, J=9.0Hz), 7.48 (1H, d, J=7.7 Hz),

EXAMPLE 676 Synthesis of1-ethyl-3,3,5-trimethyl-7-{2-[(2-methylpyridin-3-ylmethyl)amino]ethoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.85 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.59 (3H, s),3.02-3.10 (2H, m), 3.39 (3H, s), 3.65-3.76 (1H, m), 3.89 (2H,s),4.09-4.21 (3H, m), 6.73-6.75 (1H, m), 6.80-6.85 (1H, m), 7.10-7.14 (1H,m), 7.19-7.23 (1H, m), 7.65 (1H, dd, J=7.7 and 1.5Hz), 8.40-8.42 (1H, m)

EXAMPLE 677 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]nicotinamide

Using an appropriate starting material and following the procedure ofExample 459, the object compound was synthesized.

White Amorphous

¹H-NMR (CDCl₃) δppm:

0.82 (3H, s), 1.13 (3H, t, J=7.0 Hz), 1.51 (3H, s), 1.88-2.45 (2H, m),3.37 (3H, s), 3.42-3.60 (2H, m), 3.60-3.90 (3H, m), 3.95 (2H, t, J=6.2Hz), 4.01-4.27 (1H, m), 4.40 (2H, t, J=6.2 Hz), 6.40-6.67 (2H, m),667-7.43(4H, m), 7.43-7.61 (2H, m), 7.61-7.76 (2H, m), 8.13-8.78 (3H, m)

EXAMPLE 678 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-methyl-N-(2-pyridin-3-ylethyl)benzamidehydrochloride

Using an appropriate starting material and following the procedure ofExample 633, the object compound was synthesized.

White Powder

Melting Point 155.3 to 159.3° C. (dec.)

EXAMPLE 679 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-methoxy-N-(2-pyridin-3-ylethyl)isonicotinamide

Using an appropriate starting material and following the procedure ofExample 459, the object compound was synthesized.

White Powder

Melting Point 112.8 to 113.9° C.

EXAMPLE 680 Synthesis of cyclohexanecarboxylic acid[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-ylethyl)amidehydrochloride

Using an appropriate starting material and following the procedure ofExample 633, the object compound was synthesized.

White Powder

Melting Point 153.4 to 157.5° C. (dec.)

EXAMPLE 681 Synthesis ofN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)-propyl]-N-(2-pyridin-3-yl-ethyl)-acetamidehydrochloride

Using an appropriate starting material and following the procedure ofExample 633, the object compound was synthesized.

White Amorphous

¹H-NMR (DMSO-d₆) δppm:

0.73 and 0.74(3H, s), 1.01(3H, t, J=7.0 Hz), 1.32 (3H, s), 1.85-2.12(2H, m), 1.93 and 1.95(3H, s), 2.92-3.11 (2H, m), 3.12-3.95 (5H, m),3.32 (3H, s), 3.95-4.16(3H, m), 6.88-7.00 (2H, m), 7.40 (1H, dd, J=8.8and 2.7 Hz), 7.89 (1H, dt, J=8.1 and 5.5 Hz), 8.36 (1H, d, J=8.1 Hz,),8.74 (1H, d, J=5.5 Hz), 8.77-8.86(1H, m)

EXAMPLE 682 Synthesis of7-(4-amino-butoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 2, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.60-1.70 (2H, m),1.82-1.90 (2H, m), 2.80 (2H, t, J=7.0 Hz), 3.40 (3H, s), 3.64-3.76 (1H,m), 4.00 (2H, t, J=6.3 Hz), 4.12-4.24 (1H, m), 6.72 (1H, d, J=2.7 Hz),6.81 (1H, dd, J=9.0 and 2.7 Hz), 7.20 (1H, d, J=9.0 Hz)

EXAMPLE 683 Synthesis of7-(2-amino-ethoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 2, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.13 (2H, t, J=5.1Hz), 3.40 (3H, s), 3.47-3.76 (1H, m), 4.01 (2H, t, J=5.1 Hz), 4.11-4.24(1H, m), 6.75 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=9.0 and 2.8 Hz), 7.21(1H, d, J=9.0 Hz)

EXAMPLE 684 Synthesis of1,5-dimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-methylpyridin-3-ylmethyl)amino]propoxy}spiro[benzo[b][1,4]diazepine-3,1′-cyclobutane]-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 7, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

1.64 (br, 4H), 2.28 (br, 2H), 2.42 (s, 3H), 2.49 (s, 3H), 2.75 (br, 2H),2.84-2.88 (m, 4H), 3.39 (s, 3H), 3.40 (s, 3H), 3.64 (br, 2H), 3.89 (br,2H), 4.00 (br, 2H), 6.33-6.35 (m, 1H), 6.51 (br, 1H), 6.56-6.69 (m, 2H),6.89-6.92 (m, 2H), 7.47 (br, 1H), 8.32 (br, 2H).

EXAMPLE 685 Synthesis of7-[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)propoxy]-1,5-dimethylspiro[benzo[b][1,4]diazepine-3,1′-cyclobutane]-2,4-dione

Using an appropriate starting material and following the procedure ofExample 1, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.57-1.67 (m, 4H), 2.11-2.23 (m, 2H), 2.78-2.90 (m, 2H), 3.35 (s, 3H),3.37 (s, 3H), 3.93 (t, J=6.7 Hz, 2H), 4.05 (t, J=5.9 Hz, 2H), 6.61 (d,J=2.8 Hz, 1H), 6.71 (dd, J=9.0 and 2.8 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H),7.71-7.75 (m, 2H), 7.83-7.86 (m, 2H).

EXAMPLE 686 Synthesis of7-(3-Aminopropoxy)-1,5-dimethylspiro[benzo[b][1,4]diazepine-3,1′-cyclobutane]-2,4-dione

Using an appropriate starting material and following the procedure ofExample 2, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.63-1.68 (m, 4H), 1.96-2.01 (m, 2H), 2.78-2.83 (m, 2H), 2.93 (t, J=6.7Hz, 2H), 3.38 (s, 3H), 3.42 (s, 3H), 4.07 (t, J=6.2 Hz, 2H), 6.74 (d,J=2.7 Hz, 1H), 6.80 (dd, J=8.9 and 2.7 Hz, 1H), 7.16 (d, J=8.9 Hz, 1H).

EXAMPLE 687 Synthesis of1,5-Dimethyl-7-{3-[(2-methylpyridin-3-ylmethyl)amino]propoxy}spiro[benzo[b][1,4]diazepine-3,1′-cyclobutane]-2,4-dione

Using an appropriate starting material and following the procedure ofExample 77, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.62-1.68 (m, 4H), 2.00-2.05 (m, 2H), 2.57 (s, 3H), 2.82-2.91 (m, 4H),3.39 (s, 3H), 3.41 (s, 3H), 3.82 (s, 2H), 4.08 (t, J=6.1 Hz, 2H), 6.73(d, J=2.7 Hz, 1H), 6.79 (dd, J=8.9 and 2.7 Hz, 1H), 7.10 (dd, J=7.6 and4.9 Hz, 1H), 7.16 (d, J=8.9 Hz, 1H), 7.62 (dd, J=7.6 and 1.4 Hz, 1H),8.40 (dd, J=4.9 and 1.4 Hz, 1H).

EXAMPLE 688 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]thiazol-2-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm: 0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s,3H), 2.20 (br, 2H), 3.30 (s, 3H), 3.21-3.58 (m, 4H), 3.61-3.71 (m, 1H),4.00-4.11 (m, 3H), 4.42 (br, 2H), 4.81 (br, 2H), 6.69 (d, J=7.0 Hz, 1H),6.82-6.89 (m, 2H), 7.38 (d, J=9.0 Hz, 1H), 7.50-7.54 (m, 2H), 7.66-7.75(m, 2H), 7.89 (br, 2H), 8.21 (d, J=8.0 Hz, 1H).

EXAMPLE 689 Synthesis of1-ethyl-7-(3-{(3-fluorobenzyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionehydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.29 (br, 2H), 3.31(s, 3H), 3.50 (br, 4H), 3.61-3.68 (m, 1H), 4.02-4.18 (m, 3H), 4.48-4.60(m, 4H), 6.72 (d, J=7.2 Hz, 1H), 6.85-6.90 (m, 2H), 7.30-7.42 (m, 2H),7.46-7.81 (m, 7H), 8.23 (d, J=8.0 Hz, 1H).

EXAMPLE 690 Synthesis of1-ethyl-7-(3-{(3-methoxybenzyl)-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionehydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.27 (br, 2H),3.21-3.30 (m, 5H), 3.42 (s, 3H), 3.51 (br, 2H), 3.61-3.72 (m, 1H),4.02-4.18 (m, 3H), 4.38-4.61 (m, 4H), 6.73 (d, J=7.2 Hz, 1H), 6.86-6.90(m, 2H), 7.01 (d, J=8.8 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.31-7.42 (m,3H), 7.51-7.56 (m, 2H), 7.68-7.77 (m, 2H), 8.21 (d, J=8.0 Hz, 1H).

EXAMPLE 691 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]thiophen-2-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionehydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.75 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.29 (br, 2H),3.21-3.29 (m, 5H), 3.49 (br, 4H), 3.62-3.70 (m, 1H), 4.01-4.29 (m, 3H),4.48 (br, 2H), 6.72 (d, J=7.1 Hz, 1H), 6.86-6.93 (m, 2H), 7.15 (br, 1H),7.40 (d, J=8.9 Hz, 1H), 7.50-7.55 (m, 3H), 7.67-7.74 (m, 3H), 8.21 (d,J=8.0 Hz, 1H).

EXAMPLE 692 Synthesis of7-(3-{bis-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionehydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.28 (br, 2H), 3.29(s, 3H), 3.61 (br, 2H), 3.61-3.71(m, 5H), 3.95-4.09 (m, 1H), 4.17 (br,2H), 4.45 (br, 4H), 6.71-6.74 (m, 2H), 6.91-6.97 (m, 2H), 7.40 (d, J=9.0Hz, 1H), 7.49-7.57 (m, 4H), 7.67-7.74 (m, 4H), 8.15 (d, J=8.2 Hz, 2H).

EXAMPLE 693 Synthesis of1-ethyl-7-(3-{[2-(7-methoxy-2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.25 (br, 4H),3.01-3.31 (m, 4H), 3.31 (s, 3H), 3.61-3.70 (m, 1H), 4.00-4.12 (m, 5H),4.61 (br, 2H), 6.65 (d, J=7.4 Hz, 1H), 6.86-6.91 (m, 2H), 7.39 (d, J=8.9Hz, 1H), 7.47-7.53 (m, 2H), 7.65-7.74 (m, 2H), 8.08 (br, 2H), 8.21 (d,J=8.0 Hz, 1H), 8.80 (br, 2H).

EXAMPLE 694 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.28 (br, 2H),3.21-3.49 (m, 5H), 3.60-3.70 (m, 3H), 4.01-4.19 (m, 3H), 4.78 (br, 4H),6.64 (d, J=7.4 Hz, 1H), 6.88 (br, 2H), 7.30 (br, 1H), 7.39 (d, J=8.9 Hz,1H), 7.55-8.20 (m, 6H), 8.82 (br, 2H).

EXAMPLE 695 Synthesis of1-ethyl-7-{3-[(2-(6-methoxy-2-oxo-2H-quinolin-1-yl)ethyl)pyridin-4-ylmethylamino]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.17 (br, 2H),3.01-3.35 (m, 5H), 3.53-3.70 (m, 3H), 3.82 (s, 3H), 4.01-4.12 (m, 3H),4.67 (br, 4H), 6.63 (d, J=7.4 Hz, 1H), 6.83-6.89 (m, 2H), 7.21 (d, J=9.2Hz, 1H), 7.32 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.70 (br, 1H), 7.91 (d,J=9.5 Hz, 1H), 8.00 (br, 2H), 8.82 (br, 2H).

EXAMPLE 696 Synthesis of1-ethyl-7-(3-{[2-(6-methoxyquinolin-2-yloxy)ethyl]pyridin-4-ylmethylamino}propoxy)⁻3,3,5-trimethyl⁻1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.09 (br, 2H), 3.01(br, 2H), 3.31 (s, 3H), 3.70-3.90 (m, 4H), 3.98-4.18 (m, 5H), 4.33 (br,2H), 4.80 (br, 2H), 6.50 (d, J=9.6 Hz, 1H), 6.79-6.90 (m, 2H), 7.21-7.25(m, 1H), 7.30-7.39 (m, 2H), 7.85 (d, J=9.6 Hz, 1H), 8.20 (d, J=8.9 Hz,1H), 8.21 (br, 2H), 8.88 (br, 2H).

EXAMPLE 697 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo⁻3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.10 (br, 2H),2.51-2.60 (m, 2H), 2.85 (br, 4H), 3.31 (s, 3H), 3.10-3.35 (m, 2H),3.52-3.70 (m, 3H), 4.01-4.11 (m, 3H), 4.22 (br, 2H), 6.85-6.89 (m, 2H),7.00-7.02 (m, 1H), 7.13 (br, 1H), 7.19-7.24 (m, 2H), 7.40 (d, J=8.8 Hz,1H), 7.82 (br, 2H), 8.73 (br, 2H).

EXAMPLE 698 Synthesis of1-ethyl-3,3,5-trimethyl-7-{3-[(2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.08 (br, 2H), 3.05(br, 2H), 3.31 (s, 3H), 3.53-3.70 (m, 1H), 3.95-4.09 (m, 5H), 4.31 (br,4H), 6.71-6.83 (m, 2H), 6.95 (br, 1H), 7.39 (d, J=8.9 Hz, 1H), 7.45-7.47(m, 1H), 7.57-7.64 (m, 2H), 7.88 (br, 2H), 8.72 (br, 2H).

EXAMPLE 699 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{([2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.32 (br, 2H), 3.33(s, 3H), 3.26-3.37 (m, 2H), 3.43 (br, 2H), 3.62-3.70 (m, 1H), 4.00-4.13(m, 3H), 4.53 (br, 2H), 4.82 (br, 2H), 6.82-6.89 (m, 2H), 6.92-6.93 (m,1H), 7.38-7.42 (m, 2H), 7.69 (d, J=7.2 Hz, 1H), 8.09 (d, J=5.2 Hz, 1H),8.44 (br, 2H), 9.00 (br, 2H).

EXAMPLE 700 Synthesis of1-ethyl-7-(3-{[2-(8-methoxy-2-oxo-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.33 (br, 2H), 3.32(s, 3H), 3.25-3.38 (m, 2H), 3.53-3.69 (m, 3H), 3.86 (s, 3H), 4.03-4.10(m_(i) 1H), 4.14 (br, 2H), 4.65 (br, 2H), 4.81 (br, 2H), 6.64 (d, J=9.4Hz, 1H), 6.89-6.95 (m, 2H), 7.21-7.33 (m, 3H), 7.41 (d, J=8.9 Hz, 1H),7.92 (d, J=9.4 Hz, 1H), 8.14 (br, 2H), 8.68 (br, 2H).

EXAMPLE 701 Synthesis of1-ethyl-7-(3-{[2-(8-methoxyquinolin-2-yloxy)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.26 (br, 2H),3.15-3.21 (m, 2H), 3.31 (s, 3H), 3.58-3.65 (m, 1H), 3.90 (s, 3H),3.98-4.12 (m, 5H), 4.51-4.80 (m, 4H), 6.52 (d, J−9.6 Hz, 1H), 6.83-6.89(m, 2H), 7.08-7.11 (m, 1H), 7.19-7.21 (m, 1H), 7.32-7.48 (m, 2H), 7.89(d, J=9.6 Hz, 1H), 8.00 (br, 2H), 8.80 (br, 2H).

EXAMPLE 702 Synthesis of1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.16 (br, 2H), 3.09(br, 2H), 3.31 (s, 3H), 3.60-3.75 (m, 3H), 3.91-4.08 (m, 3H), 4.38 (br,4H), 6.77-6.87 (m, 3H), 6.94 (br, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.70 (br,1H), 7.90 (br, 1H), 8.11 (br, 2H), 8.84 (br, 2H).

EXAMPLE 703 Synthesis of1-ethyl-7-(3-{[2-(6-methoxy-2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.16 (br,2H),2.48-2.54 (m, 2H), 2.77 (br, 2H), 3.31 (s, 3H), 3.25-3.34 (m, 2H),3.53-3.69 (m, 3H), 3.76 (s, 3H), 3.98-4.10 (m, 3H), 4.33 (br, 2H), 4.74(br, 2H), 6.60 (d, J=8.3 Hz, 1H), 6.74 (br, 1H), 6.82-6.91 (m, 2H), 7.13(d, J=8.3 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.98 (br, 2H), 8.80 (br, 2H).

EXAMPLE 704 Synthesis of1-ethyl-7-(3-{[2-(7-methoxy-2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride

Using an appropriate starting material and following the procedure ofExample 6, the object compound was synthesized.

¹H-NMR (DMSO-d₆) δppm:

0.74 (s, 3H), 1.01 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.22 (br, 2H),2.48-2.53 (m, 2H), 2.83 (br, 2H), 3.10-3.25 (m, 2H), 3.31 (s, 3H),3.53-3.63 (m, 3H), 3.73 (s, 3H), 4.00-4.10 (m, 3H), 4.32 (br, 2H), 4.61(br, 2H), 6.74-6.77 (m, 1H), 6.84 6.91 (m, 3H), 7.16 (br, 1H), 7.40 (d,J=8.9 Hz, 1H), 8.00 (br, 2H), 8.83 (br, 2H).

EXAMPLE 704A Synthesis of1,3,3-trimethyl-8-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 8, the object compound was synthesized. (CDCl₃) δppm:

1.05 (3H, br), 1.52 (3H, br), 1.88-1.93 (2H, m), 2.71 (2H, t, J=6.7 Hz),2.88 (2H, t, J=6.0 Hz), 3.41 (3H, s), 3.67 (2H, s), 3.84 (2H, t, J=5.9Hz), 4.10 (2H, t, J=6.0 Hz), 6.41 (1H, d, J=7.3 Hz), 6.52 (1H, dd, J=8.8and 2.6 Hz), 6.61 (1H, d, J=2.6 Hz), 6.87 (1H, d, J=8.8 Hz), 6.97 (1H,d, J=7.3 Hz), 7.08 (2H, d, J=5.7 Hz), 7.49-7.53 (2H, m), 7.64-7.69 (1H,m), 7.78 (1H, br), 8.26 (2H, d, J=5.7 Hz), 8.38 (1H, d, J=7.3 Hz).

EXAMPLE 704B Synthesis of1,3,3-trimethyl-8-{3-[2-(1-oxo-1H-isoquinolin-2-yl)ethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Using an appropriate starting material and following the procedure ofExample 18, the object compound was synthesized.

¹H-NMR (CDCl₃) δppm:

1.05 (3H, br), 1.55 (3H, br), 1.93-1.99 (2H, m), 2.86 (2H, t, J=6.7 Hz),3.06 (2H, t, J=6.2 Hz), 3.43 (3H, s), 4.01 (2H, t, J=6.2 Hz), 4.09-4.15(3H, m), 6.46 (1H, d, J=7.4 Hz), 6.66-6.72 (2H, m), 6.87 (1H, d, J=8.6Hz), 7.11 (1H, d, J=7.3 Hz), 7.46-7.51 (2H, m), 7.61-7.67 (1H, m), 7.87(1H, br), 8.41 (1H, d, J=8.0 Hz).

Using appropriate starting materials and following the procedures of theabove-mentioned Examples, the compounds shown in Tables 34 to 76 wereprepared.

TABLE 34

MS Example No. R101 R102 R103 R104 R105 (M +1) Example 705 —H —H —H —H—H 501 Example 706 —H —H —C₆H₅ —H —H 577 Example 707 —H —H —OCH₃ —H —H531 Example 708 —H —OCH₃ —H —H —H 531 Example 709 —H —H —NHCOCH₃ —H —H558 Example 710 —Cl —H —H —H —H 535 Example 711 —H —Cl —H —H —H 535Example 712 —H —H —Cl —H —H 535 Example 713 —OCH₃ —H —H —H —H 531Example 714 —H —C₆H₅ —H —H —H 577 Example 715 —H —H -2-THIENYL —H —H 583Example 716 —H —H -3-PYRIDYL —H —H 578 Example 717 —H -3-PYRIDYL —H —H—H 578 Example 718 -3-PYRIDYL —H —H —H —H 578

TABLE 35

MS Example No. R101 R102 R103 R104 R105 (M +1) Example 719 —H —H

—H —H 568 Example 720 —H —H

—H —H 567 Example 712 —H

—H —H —H 567 Example 722 —H —H

—H —H 579 Example 723 —H

—H —H —H 579 Example 724 —H —H

—H —H 584

TABLE 36

MS Example No. R106 (M + 1) Example 725 -3-FURYL 491 Example 726-2-PYRIDYL 502 Example 727 -3-PYRIDYL 502 Example 728 -4-PYRIDYL 502Example 729 -2-THIENYL 507 Example 730 -3-THIENYL 507 Example 731—CH═CHC₆H₅ (trans) 527 Example 732 -2-FURYL 491 Example 733 —CH₂C₆H₅ 515Example 734 —CH(CH₃)C₆H₅ 529 Example 735 —(CH₂)₂C₆H₅ 529 Example 736-2-BENZTHIAZOLYL 558

TABLE 37

MS Example No. R106 (M + 1) Example 737

491 Example 738

505 Example 739

521 Example 740

541 Example 741

552 Example 742

552 Example 743

567 Example 744

554 Example 745

541

TABLE 38

MS Example No. R106 (M + 1) Example 746

547 Example 747

584 Example 748

517 Example 749

508 Example 750

571 Example 751

541 Example 753

519 Example 753

582

TABLE 39

MS Example No. R106 (M + 1) Example 754

555 Example 755

505 Example 756

545 Example 757

557 Example 758

551 Example 759

545 Example 760

540 Example 761

543

TABLE 40

MS Example No. R106 (M + 1) Example 762

570 Example 763

541 Example 764

545 Example 765

561 Example 766

575 Example 767

519 Example 768

539 Example 769

505 Example 770

541

TABLE 41

MS Example No. R106 (M + 1) Example 771

541 Example 772

552 Example 773

574 Example 774

552 Example 775

557 Example 776

516 Example 777

521 Example 778

555

TABLE 42

MS Example No. R106 (M + 1) Example 779

520 Example 780

584 Example 781

522 Example 782

559 Example 783

559 Example 784

536 Example 785

555 Example 786

554 Example 787

581

TABLE 43

MS Example No. R106 (M + 1) Example 788

581 Example 789

542 Example 790

558 Example 791

556 Example 792

505 Example 793

545 Example 794

584

TABLE 44

MS Example No. R106 (M + 1) Example 795

516 Example 796

516 Example 797

516 Example 798

516 Example 799

581 Example 800

574 Example 801

567 Example 802

520 Example 803

552

TABLE 45

MS Example No. R106 (M + 1) Example 804

584 Example 805

558 Example 806

582 Example 807

581 Example 808

598 Example 809

558 Example 810

555 Example 811

541

TABLE 46

MS Example No. R106 (M + 1) Example 812

573 Example 813

581 Example 814

587 Example 815

584 Example 816

571 Example 817

565 Example 818

598 Example 819

553

TABLE 47

Example MS No. R106 (M + 1) Example 820

571 Example 821

573 Example 822

505 Example 823

541 Example 824

625 Example 825

595 Example 826

516 Example 827

536

TABLE 48

Example MS No. R106 (M + 1) Example 828

520 Example 829

505

TABLE 49

Example MS No. R106 (M + 1) Example 830

554 Example 831

598 Example 832

559 Example 833

569 Example 834

569 Example 835

598 Example 836

625 Example 837

567

TABLE 50

Example MS No. R106 (M + 1) Example 838

585 Example 839

585 Example 840

609 Example 841

550 Example 842

534 Example 843

584 Example 844

584 Example 845

626

TABLE 51

Example MS No. R106 (M + 1) Example 846

626 Example 847

519 Example 848

596

TABLE 52

Example No. R201 R202 R203 R204 R205 MS (M + 1) Example 849 —H —H —OCH₃—H —H 661 Example 850 —H —H —Cl —H —H 665 Example 851 —H —H —H —H —CH₃645 Example 852 —H —H —F —H —H 649 Example 853 —H —H —H —H —Cl 665Example 854 —H —H —H —H —CO₂CH₃ 689 Example 855 —CN —H —H —H —H 656Example 856 —H —OCH₃ —H —H —H 661 Example 857 —H —F —H —H —H 649 Example858 —H —H —H —H —F 649 Example 859 —H —CH₃ —H —H —H 645 Example 860 —H—Cl —H —H —H 665 Example 861 —H —H —H —H —H 631 Example 862 —H —H—NHCOCH₃ —H —H 688 Example 863 —H —H —CH₃ —H —H 645 Example 864 —H —CO₂H—H —H —H 675 Example 865 —H —CN —H —H —H 656 Example 866 —H —H —CN —H —H656

TABLE 53

Example No. R201 R202 R203 R204 R205 MS (M + 1) Example 867 —H —H

—H —H 698 Example 868 —H —H

—H —H 711 Example 869 —H —H

—H —H 725 Example 870 —H

—H —H —H 711 Example 871 —H —H

—H —H 714 Example 872 —H

—H —H —H 711 Example 873 —H

—H —H —H 709

TABLE 54

Example No. R201 R202 R203 R204 R205 MS (M + 1) Example 874 —H

—H —H —H 728 Example 875 —H —H

—H —H 709 Example 876 —H —H

—H —H 728 Example 877 —H

—H —H —H 723

TABLE 55

Example No. R206 MS (M + 1) Example 878 -2-THIENYL 637 Example 879—CH₂C₆H₅ 645 Example 880 -3-THIENYL 637 Example 881 -2-FURYL 621

TABLE 56

Example No. R206 MS (M + 1) Example 882

682 Example 883

635 Example 884

689 Example 885

671 Example 886

702 Example 887

696 Example 888

682

TABLE 57

Example No. R206 MS (M + 1) Example 889

683 Example 890

650 Example 891

705 Example 892

709 Example 893

695 Example 894

684 Example 895

665

TABLE 58

Example No. R206 MS (M + 1) Example 896

651 Example 897

693 Example 898

692 Example 899

671 Example 900

711 Example 901

649 Example 902

725 Example 903

712

TABLE 59

Example No. R206 MS (M + 1) Example 904

663 Example 905

679 Example 906

711 Example 907

725 Example 908

703 Example 909

635 Example 910

703

TABLE 60

Example No. R206 MS (M + 1) Example 911

635 Example 912

684 Example 913

666 Example 914

659 Example 915

679 Example 916

663 Example 917

717 Example 918

675

TABLE 61

Example No. R206 MS (M + 1) Example 919

673 Example 920

704 Example 921

636 Example 922

684 Example 923

703 Example 924

686 Example 925

663

TABLE 62

Example No. R206 MS (M + 1) Example 926

714 Example 927

700 Example 928

702 Example 929

703 Example 930

702 Example 931

663 Example 932

707

TABLE 63

Example No. R206 MS (M + 1) Example 933

702 Example 934

709 Example 935

679 Example 936

649 Example 937

688 Example 938

670 Example 939

670 Example 940

673

TABLE 64

MS Example (M + No. R301 R302 R303 R304 R305 1) Example —H —H —H —H —H529 941 Example —H —H —CH₃ —H —H 543 942 Example —H —H —Cl —H —H 563 943Example —H —H —F —H —H 547 944 Example —H —H —OCH₃ —H —H 559 945 Example—OCH₃ —H —H —H —H 559 946 Example —Cl —H —H —H —H 563 947 Example —CH₃—H —H —H —H 543 948 Example —F —H —H —H —H 547 949 Example —H —OCH₃ —H—H —H 559 950 Example —H —Cl —H —H —H 563 951 Example —H —CH₃ —H —H —H543 952 Example —H —F —H —H —H 547 953

TABLE 65

Example No. R306 MS (M + 1) Example 954 —CH₂OC₆H₅ 559 Example 955—(CH₂)₂C₆H₅ 557 Example 956 —CH═CHC₆H₅ (trans) 555 Example 957-2-PYRIDYL 530 Example 958 -3-PYRIDYL 530 Example 959 -4-PYRIDYL 530Example 960 -2-FURYL 519 Example 961 -2-THIENYL 535 Example 962 -3-FURYL519 Example 963 -3-THIENYL 535 Example 964 -2-BENZTHIAZOLYL 586

TABLE 66

Example No. R306 MS (M + 1) Example 965

558 Example 966

544 Example 967

544 Example 968

544 Example 969

549 Example 970

549 Example 971

585 Example 972

556 Example 973

556

TABLE 67

Example No. R306 MS (M + 1) Example 974

568 Example 975

568 Example 976

580 Example 977

580 Example 978

580 Example 979

580 Example 980

580 Example 981

580

TABLE 68

Example No. R306 MS (M + 1) Example 982

569 Example 983

582 Example 984

582 Example 985

556 Example 986

598 Example 987

596 Example 988

586 Example 989

532

TABLE 69

Example No. R306 MS (M + 1) Example 990

531 Example 991

581 Example 992

569 Example 993

536 Example 994

569 Example 995

545 Example 996

569 Example 997

569

TABLE 70

Example No. R306 MS (M + 1) Example 998

571 Example 999

571 Example 1000

569 Example 1001

568 Example 1002

568 Example 1003

568 Example 1004

587

TABLE 71

Example No. R306 MS (M + 1) Example 1005

581 Example 1006

581 Example 1007

587 Example 1008

600 Example 1009

533 Example 1010

533 Example 1011

584 Example 1012

533

TABLE 72

Example No . R306 MS (M + 1) Example 1013

578 Example 1014

561 Example 1015

547 Example 1016

563 Example 1017

583 Example 1018

533 Example 1019

569 Example 1020

569

TABLE 73

Example No . R306 MS (M + 1) Example 1021

569 Example 1022

531 Example 1023

573 Example 1024

581 Example 1025

569 Example 1026

582 Example 1027

580 Example 1028

598

TABLE 74

Example No. R306 MS (M + 1) Example 1029

531 Example 1030

582 Example 1031

580 Example 1032

569 Example 1033

545 Example 1034

561 Example 1035

587 Example 1036

583

TABLE 75

Example No. R306 MS (M + 1) Example 1037

582 Example 1038

582 Example 1039

533 Example 1040

584 Example 1041

581 Example 1042

531 Example 1043

580

TABLE 76

Example No. R306 MS (M + 1) Example 1044

580 Example 1045

568 Example 1046

548 Example 1047

533Pharmacological Test 1

(1) Production of Human Kv1.5-Expressing CHO-K1 Cell Lines

CHO-K1 cell lines stably expressing human Kv1.5 channels were preparedin the following manner.

Full-length human Kv1.5 cDNA was cloned from a human heart cDNA library(produced by Stratagene). The obtained human Kv1.5 sequence correspondsto the sequence described in FASEB J. 5, 331-337 (1991).

The obtained human Kv1.5 cDNA was inserted into a plasmid encoding a CMVpromoter and a G418 resistance marker to produce a Kv1.5 expressionvector. The human Kv1.5 expression vector was transfected into CHO-K1cells by the lipofectamine method. After culturing the cells in an F-12medium (produced by Invitrogen Corp.) containing 10% FBS (produced byInvitrogen Corp.) for 3 or 4 days, the medium was replaced with aFBS-containing F-12 medium that included 1,000 μg/ml of G418 (producedby Invitrogen Corp.), and single colonies were isolated. The amount ofKv1.5 channel expression in the single colonies was quantified at themRNA level by RT-PCR and then quantified at the protein level by westernblotting. Finally, the expressed current was analyzed by patch clampmethod. Cell lines expressing a current of 200 pA or more per cell wereselected as channel-expressing cell lines for activity measurement bypatch clamp method.

(2) Production of CHO Cell Line Expressing Human GIRK1/4

CHO cell lines stably expressing human GIRK1/4 channels were prepared inthe following manner.

Full-length human GIRK1 cDNA was cloned from HuH cell- and HeLacell-derived cDNA libraries. Full-length GIRK4 cDNA was amplified from ahuman heart cDNA library (produced by Clontech Laboratories, Inc.) byPCR using synthetic primers shown in Table 1, and cloned into the Eco-RIrestriction enzyme site of pCR-Blunt (produced by InvitrogenCorporation) or into the HincII site of pUC118 (produced by Takara Bio,Inc.).

TABLE 77 Primer Sequence hGIRK1-S 5′-ATGTCTGCACTCCGAAGGAAATTTG-3′SEQ ID No. 1 hGIRK1-A 5′-TTATGTGAAGCGATCAGAGTTC-3′ SEQ ID No. 2hGIRK1-F2 5′-GCAGGGTACCCCTTCGTATTATGTCTGCACTCC-3′ SEQ ID No. 3 hGIRK1-A35′-GGTGTCTGCCGAGATTTGA-3′ SEQ ID No. 4 hGIRK1-A45′-CCGAGTGTAGGCGATCACCC-3′ SEQ ID No. 5 hGIRK4-S5′-ATGGCTGGCGATTCTAGGAATGCC-3′ SEQ ID No. 6 hGIRK4-A5′-TCTCACCGAGCCCCTGGCCTCCC-3′ SEQ ID No. 7 hGIRK4-S25′-AACCAGGACATGGAGATTGG-3′ SEQ ID No. 8 hGIRK4-A25′-GAGAACAGGAAAGCGGACAC-3′ SEQ ID No. 9

The obtained human GIRK1 and GIRK4 cDNA sequences correspond to knownsequences (NCBI database: GIRK1 (NM_(—)002239) and GIRK4 (NM_(—)000890)respectively). The obtained GIRK1 and GIRK4 cDNA sequences were clonedinto the Eco-RI restriction enzyme site of pCR-Blunt (available fromInvitrogen Corporation) or into the HincII site of pUC118 (availablefrom Takara Bio, Inc.). A GIRK4 expression vector was constructed byinsertion into the BamHI-XhoI site of pcDNA5/FRT. A GIRK1 expressionvector was constructed by insertion into the KpnI-XhoI site of pcDNA3. 1(+) or pCAG_neo. FLP-IN-CHO cells (produced by Invitrogen Corporation)were transfected with human GIRK1 and GIRK4 expression vectors by usingLipofectamine 2000 (produced by Invitrogen Corporation) according to theprotocol enclosed with the reagent or using an electronic inductionmethod (“Nucleofector Kit-T”, produced by Amaxa). First, the cellstransfected with the GIRK4 expression vector were cultured in a 10%serum-containing F12 medium (produced by Sigma) supplemented with 600μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C.Then the cells expressing GIRK4 were transfected with the GIRK1expression vector and were cultured in 10% serum-containing F12 mediumsupplemented with 350 μg/ml of G418 and 600 μg/ml of hygromycin in anincubator with 5% carbon dioxide at 37° C. to select GIRK1/4 expressingcell lines. Cell populations whose growth was observed after about 2weeks were isolated using cloning rings, and the obtained singlecolonies were proliferated. RNA was extracted from single colonies, andsingle-stranded cDNA was synthesized by a cDNA synthesis kit (producedby Invitrogen Corporation), and the amount of expression was quantifiedat the mRNA level by real-time PCR (Applied Biosystems, Ltd.). Finally,the expressed current was analyzed by patch clamp method describedbelow. The cell lines expressing a current of 500 pA or more per cellwere selected as channel-expressing cell lines for activity measurementby patch clamping method.

(3) Measurement of Ion Channel Current by Patch Clamp Method (HumanKv1.5-Expressing CHO-K1 Cell Line)

An experiment was carried out using a patch clamp setup at roomtemperature (20 to 26° C.). A perfusion chamber having a diameter of 20nun (flow rate: about 5 ml/min) was mounted on the stage of aphase-contrast inverted microscope (produced by Nikon Corporation)placed on a vibration isolated table. A poly-L-lysine (produced bySigma) -coated coverslip (diameter: 15 mm, produced by Matsunami GlassInd., Ltd.) on which human Kv1.5-expressing cells were cultured wasplaced in the perfusion chamber.

Depolarizing stimulation pulses were applied and ionic current wasrecorded by using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, producedby HEKA) and a personal computer (manufactured by IBM Corp.) in whichsoftware for data acquisition and analysis of ion channel current (PULSE8.77, produced by HEKA) was installed. The current was measured in thewhole-cell configuration of the patch-clamp technique. The tip(resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced bySutter Instrument Co.) was gently placed on the cell membrane by using athree-dimensional mechanical micromanipulator (produced by Shoshin EMCorporation). Weak suction resulted in giga seal formation (the pipetteresistance increased to more than 1 GΩ). Subsequently, stronger suctionwas applied to break the cell membrane. The capacitative current derivedfrom the cell membrane was corrected using a patch clamp amplifier.Subsequently, the series resistance (Rs) between the pipette and theinterior of the cell was measured and corrected.

The composition of the extracellular solution used is shown below.Unless otherwise specified, these components were obtained from WakoPure Chemical Industries, Ltd.

NaCl 140 mM, KCl 40 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, NaH₂PO₄ 0.33 mM, HEPES5 mM Glucose 5.5 mM (pH = 7.4)

Each test compound was prepared as a 1000-fold concentrated stocksolution that was dissolved in DMSO and then diluted in theextracellular solution.

The composition of the electrode internal solution used is shown below.Unless otherwise specified, these components were obtained from WakoPure Chemical Industries, Ltd.

KOH 100 mM, KCl 40 mM, Aspartic acid 70 mM, MgCl₂ 1 mM, MgATP 5 mM, K₂creatine phosphate 5 mM, HEPES 5 mM EGTA 5 mM (pH = 7.2)

(4) Measurement of Ion Channel Current by Patch Clamp Method (HumanGIRK1/4-Expressing CHO-K1 Cell Line)

An experiment was carried out using a patch clamp setup at roomtemperature (20 to 26° C.). A perfusion chamber having a diameter of 20mm (flow rate: about 5 ml/min) was mounted on the stage of aphase-contrast inverted microscope (produced by Nikon Corporation)placed on a vibration isolation table. A poly-L-lysine (produced bySigma) -coated coverslip (diameter: 15 mm, produced by Matsunami GlassInd., Ltd.) on which human GIRK1/4-expressing cells were cultured wasplaced in the perfusion chamber.

Hyperpolarizing stimulation pulses were applied and ionic current wasrecorded using a patch clamp amplifier (EPC-7 or EPC-7 PLUS,manufactured by HEKA) and a personal computer (manufactured by IBMCorp.) in which software for data acquisition and analysis of ionchannel current (PULSE 8.77, manufactured by HEKA) was installed. Thecurrent was measured in the whole-cell configuration of the patch-clamptechnique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glasspipette (produced by Sutter Instrument Co.) was gently placed on thecell membrane by using a three-dimensional mechanical micromanipulator(produced by Shoshin EM Corporation). Weak suction resulted in giga sealformation (the pipette resistance increased to more than 1 GΩ).Subsequently, stronger suction was applied to break the cell membrane.The capacitative current derived from the cell membrane was correctedusing a patch clamp amplifier. Subsequently, the series resistance (Rs)between the pipette and the interior of the cell was measured andcorrected.

The composition of the extracellular solution used is shown below.Unless otherwise specified, these components were obtained from WakoPure Chemical Industries, Ltd.

NaCl 140 mM, KCl 4 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, NaH₂PO₄ 0.33 mM, HEPES5 mM Glucose 5.5 mM (pH = 7.4)

Each test compound was prepared as a 1000-fold concentrated stocksolution that was dissolved in DMSO and then diluted in theextracellular solution.

The composition of the electrode internal solution used is shown below.Unless otherwise specified, these components were obtained from WakoPure Chemical Industries, Ltd.

KOH 100 mM, KCl 40 mM, Aspartic acid 70 mM, MgCl₂ 1 mM, MgATP 5 mM, K₂creatine phosphate 5 mM, HEPES 5 mM EGTA 5 mM (pH = 7.2)

(5) Measurement of Human Kv1.5 Current

While the membrane potential was holded at −80 mV, depolarizing pulses(−80 mV for 0.05 seconds→+40 mV for 0.2 seconds→−40 mV for 0.2seconds→−80 mV for 0.05 seconds) were applied at a stimulation frequencyof 1 Hz to measure Kv1.5 channel current. More specifically, first,while perfusing an extracellular solution containing 0.1% DMSO andholding the membrane potential at −80 mV, depolarizing pulses wereapplied. The current obtained during the pulse application was recordedas a current in the absence of the test compounds. Subsequently, whileperfusing an extracellular solution containing 0.1 μM of a test compoundand holding the membrane potential at −80 mV, depolarizing pulses wereapplied. After the inhibitory effect of the test compound had beenstabilized, the current was recorded. The same procedure was repeatedusing an extracellular solution containing 1 μl of the test compound andthen using an extracellular solution containing 10 μM of the testcompound. The current obtained using the solution containing the testcompound at each concentration was recorded.

The data was analyzed by using the step end current recorded during the+40 mV depolarizing stimulation. The “step end current” refers to theaverage current flowing for a period of 195 to 199 milliseconds from thestart of the +40 mV depolarizing pulse stimulation.

Using the step end current in the presence of the test compound and thestep end current in the absence of the test compound, the relativecurrent in the solution containing the test compound at eachconcentration was calculated according to the following formula:Relative current=(Step end current in the presence of the testcompound)/(Step end current in the absence of the test compound)

(6) Measurement of Human GIRK1/4 Current

While the membrane potential was holded at −80 mV, hyperpolarizingpulses (−80 mV for 0.05 seconds→=120 mV for 0.2 seconds→=80 mV for 0.05seconds) were applied at a stimulation frequency of 1 Hz to measureGIRK1/4 channel current. More specifically, first, while perfusing anextracellular solution containing 0.1% DMSO and maintaining the membranepotential at −80 mV, hyperpolarizing pulses were applied. The currentobtained during the pulse application was recorded as the current in theabsence of the test compounds. Subsequently, while perfusing anextracellular solution containing 0.1 μM of a test compound andmaintaining the membrane potential at −80 mV, hyperpolarizing pulseswere applied. After the inhibitory effect of the test compound had beenstabilized, the current was recorded. The same procedure was repeatedusing an extracellular solution containing 1 μM of the test compound andthen using an extracellular solution containing 10 μM of the testcompound. The current obtained using the solution containing the testcompound at each concentration were recorded.

The data was analyzed by using the step end current recorded during the−120 mV depolarizing stimulation. The “step end current” refers to theaverage current flowing for a period of 195 to 199 milliseconds from thestart of the −120 mV depolarizing pulse stimulation.

Using the step end current in the presence of the test compound and thestep end current in the absence of the test compound, the relativecurrent in the solution containing the test compound at eachconcentration was calculated according to the following formula:Relative current=(Step end current in the presence of the testcompound)/(Step end current in the absence of the test compound)(7) Calculation of Inhibitory Activity on Kv1.5 Channel Ionic Currentand GIRK1/4 Channel Current

The concentration for 50% inhibition of Kv1.5 channel current or GIRK1/4channel current (IC₅₀ value) was calculated according to the followingnonlinear regression equation:Relative current=1/(1+[Concentration of the compound]/IC₅₀)^(nH) whereinnH is the Hill coefficient.

Table 78 shows the test results.

TABLE 78 Test Compound KV1.5 IC₅₀ (μM) GIRK1/4 IC₅₀(μM) Compound ofExample 8 0.40 0.93 Compound of Example 10 0.58 3.6 Compound of Example14 0.58 0.72 Compound of Example 19 0.54 1.4 Compound of Example 23 0.180.25 Compound of Example 31 1.30 2.90 Compound of Example 45 0.69 2.15Compound of Example 50 0.25 0.46 Compound of Example 51 0.21 1.5Compound of Example 54 0.28 0.97 Compound of Example 63 0.24 0.92Compound of Example 68 0.38 5.1 Compound of Example 85 0.15 0.15Compound of Example125 0.19 0.091 Compound of Example132 0.27 0.27Compound of Example 200 0.29 0.59 Compound of Example 229 0.16 0.69Compound of Example 242 0.18 0.22 Compound of Example 380 0.16 0.49Compound of Example 395 0.19 0.33 Compound of Example 398 0.22 0.49Compound of Example 417 0.18 0.98 Compound of Example 464 0.44 3.20Compound of Example 551 0.39 5.20 Compound of Example 568 0.42 0.05Compound of Example 573 0.33 1.50 Compound of Example 575 0.44 0.50Compound of Example 590 0.46 2.40 Compound of Example 595 0.50 0.79Compound of Example 611 0.31 0.37 Compound of Example 628 0.98 2.50Compound of Example 629 0.76 0.17 Compound of Example 633 1.10 8.40Compound of Example 634 0.36 0.49

1. A benzodiazepine compound of Formula (1)

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, andR⁴ are each independently hydrogen or lower alkyl; R² and R³ may belinked to form lower alkylene; A¹ is lower alkylene optionallysubstituted with one or more hydroxy; and R⁵ is group represented by

wherein R⁶ and R⁷ are each independently hydrogen, lower alkyl, cyclolower alkyl, phenyl, naphthyl, furyl, thienyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, pyrrolyl, triazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazo[2,1-b]thiazolyl, thieno[2,3-b]pyrazinyl,2,3-dihydroimidazo[2,1-b]thiazolyl, benzothiazolyl, indolyl,imidazo[1,2-a]pyridyl, benzothienyl, benzimidazolyl,2,3-dihydrobenzo[b]furyl, benzofuryl, indazolyl, furo[2,3-c]pyridyl,furo[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl,thieno[2,3-b]pyridyl, benzo[1,3]dioxolyl, benzisoxazolyl,pyrazolo[2,3-a]pyridyl, indolizinyl, 2,3-dihydroindolyl, isoquinolyl,1,2,3,4-tetrahydro-1H-isoquinolyl, carbostyril, 3,4-dihydrocarbostyril,quinolyl, chromanyl, 5,6,7,8-tetrahydroisoquinolyl,3,4-dihydro-1H-isoquinolyl, naphthyridinyl, 1,4-benzodioxanyl,cinnolinyl, quinoxalinyl, or 2,3-dihydrobenz-1,4-oxazinyl, each of whichis optionally substituted with one or more substituents selected fromthe group consisting of the following (4-1) to (4-32); (4-1) cyano,(4-2) hydroxy, (4-3) halogen, (4-4) lower alkyl optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, imidazolyl, morpholinyl, and lower alkoxy, (4-5) lower alkoxyoptionally substituted with one or more substituents selected from thegroup consisting of amino and lower alkyl amino, (4-6) pyridyl, (4-7)thienyl, (4-8) piperazinyl optionally substituted with one or more loweralkyl, (4-9) phenyl optionally substituted with one or more substituentsselected from the group consisting of amino and lower alkoxy, (4-10)pyrazolyl optionally substituted with one or more lower alkyl, (4-11)pyrimidinyl optionally substituted with one or more lower alkyl, (4-12)piperidyl optionally substituted with one or more lower alkyl, (4-13)furyl, (4-14) carboxy, (4-15) lower alkoxycarbonyl, (4-16) aminooptionally substituted with one or more substituents selected from thegroup consisting of lower alkanoyl, lower alkylsulfonyl, and loweraykyl, (4-17) lower alkylthio, (4-18) triazolyl, (4-19) imidazolyl,(4-20) pyrrolidinyl optionally substituted with one or more oxo, (4-21)lower alkylsulfonyl, (4-22) lower alkylenedioxy optionally substitutedwith one or more halogen, (4-23) nitro, (4-24) oxazolyl, (4-25)thiazolyl optionally substituted with one or more lower alkyl, (4-26)sulfo, (4-27) pyridyloxy, (4-28) lower alkylenedioxy, (4-29) loweralkanoylamino, (4-30) oxo, (4-31) morpholinyl, and (4-32) loweralkanoyl; X_(A) and X_(B) are each independently bond, lower alkylene,lower alkenylene, —CO—, —SO₂—, —SO₂-lower alkylene, —CO-lower alkylene,—CO-lower alkenylene, lower alkylene-N(lower alkyl)-CO-lower alkylene,lower alkylene-N(lower alkyl)-, lower alkylene-N(lower alkyl)-CO— orlower alkylene-O—.
 2. The benzodiazepine compound of Formula (1) or apharmaceutically acceptable salt thereof according to claim 1, whereinR⁶ and R⁷ are each one of the following (1) to (52): (1) hydrogen, (2)lower alkyl, (3) cyclo lower alkyl, (4) phenyl optionally substitutedwith one or more substituents selected from the group consisting of thefollowing (4-1) to (4-25): (4-1) cyano, (4-2) hydroxy, (4-3) halogen,(4-4) lower alkyl optionally substituted with one or more substituentsselected from the group consisting of halogen, imidazolyl andmorpholinyl, (4-5) lower alkoxy optionally substituted with one or moresubstituents selected from the group consisting of amino and lower alkylamino, (4-6) pyridyl, (4-7) thienyl, (4-8) piperazinyl optionallysubstituted with one or more lower alkyl, (4-9) phenyl, (4-10) pyrazolyloptionally substituted with one or more lower alkyl, (4-11) pyrimidinyloptionally substituted with one or more lower alkyl, (4-12) piperidyloptionally substituted with one or more lower alkyl, (4-13) furyl,(4-14) carboxy, (4-15) lower alkoxycarbonyl, (4-16) amino optionallysubstituted with one or more substituents selected from the groupconsisting of lower alkanoyl and lower alkylsulfonyl, (4-17) loweralkylthio, (4-18) triazolyl, (4-19) imidazolyl, (4-20) pyrrolidinyloptionally substituted with one or more oxo, (4-21) lower alkylsulfonyl,(4-22) lower alkylenedioxy optionally substituted with one or morehalogen, (4-23) nitro, (4-24) oxazolyl, and (4-25) thiazolyl optionallysubstituted with one or more lower alkyl, (5) naphthyl, (6) furyloptionally substituted with one or more substituents selected from thegroup consisting of lower alkyl optionally substituted with halogen,carboxy, sulfo, pyridyloxy, lower alkoxycarbonyl and phenyl, (7) thienyloptionally substituted with one or more substituents selected from thegroup consisting of lower alkyl, lower alkylenedioxy, carboxy, halogen,pyridyl, lower alkoxy, lower alkoxycarbonyl, oxazolyl and furyl, (8)imidazolyl optionally substituted with one or more substituents selectedfrom the group consisting of phenyl, lower alkyl and halogen, (9)pyrazolyl optionally substituted with one or more substituents selectedfrom the group consisting of lower alkyl optionally substituted withhalogen, halogen, phenyl optionally substituted with lower alkoxy, furyland thienyl, (10) oxazolyl optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl andphenyl, (11) isoxazolyl optionally substituted with one or moresubstituents selected from the group consisting of phenyl, lower alkyl,thienyl and furyl, (12) thiazolyl optionally substituted with one ormore substituents selected from the group consisting of lower alkyloptionally substituted with lower alkoxy, phenyl and loweralkanoylamino, (13) pyrrolyl optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl and loweralkoxycarbonyl, (14) triazolyl optionally substituted with one or morelower alkyl, (15) pyridyl optionally substituted with one or moresubstituents selected from the group consisting of lower alkyloptionally substituted with halogen, oxo, hydroxy, lower alkoxy,halogen, pyrrolidinyl, morpholinyl and thienyl, (16) pyrimidinyloptionally substituted with one or more substituents selected from thegroup consisting of lower alkyl and phenyl, (17) pyridazinyl, (18)pyrazinyl, (19) imidazo[2,1-b]thiazolyl optionally substituted with oneor more halogen, (20) thieno[2,3-b]pyrazinyl, (21)2,3-dihydroimidazo[2,1-b]thiazolyl optionally substituted with one ormore phenyl, (22) benzothiazolyl optionally substituted with one or morelower alkyl, (23) indolyl optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl, loweralkanoyl and halogen, (24) imidazo[1,2-a]pyridyl optionally substitutedwith one or more lower alkyl, (25) benzothienyl optionally substitutedwith one or more lower alkyl, (26) benzimidazolyl optionally substitutedwith one or more lower alkyl, (27) 2,3-dihydrobenzo[b]furyl, (28)benzofuryl optionally substituted with one or more halogen, (29)indazolyl optionally substituted with one or more lower alkyl, (30)furo[2,3-c]pyridyl optionally substituted with one or more substituentsselected from the group consisting of oxo and lower alkyl, (31)furo[3,2-c]pyridyl optionally substituted with one or more substituentsselected from the group consisting of oxo, lower alkyl optionallysubstituted with halogen, halogen, furyl, pyridyl and phenyl optionallysubstituted with one or more substituents selected from the groupconsisting of amino and lower alkoxy, (32) thieno[2,3-c]pyridyloptionally substituted with one or more substituents selected from thegroup consisting of oxo group and lower alkyl, (33) thieno[3,2-c]pyridyloptionally substituted with one or more substituents selected from thegroup consisting of oxo and lower alkyl, (34) thieno[2,3-b]pyridyl, (35)benzo[1,3]dioxolyl optionally substituted with one or more halogen, (36)benzisoxazolyl, (37) pyrazolo[2,3-a]pyridyl, (38) indolizinyl, (39)2,3-dihydroindolyl optionally substituted with one or more substituentsselected from the group consisting of oxo, lower alkyl and loweralkanoyl, (40) isoquinolyl optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl, halogenand oxo, (41) 1,2,3,4-tetrahydro-1H-isoquinolyl optionally substitutedwith one or more oxo, (42) carbostyril optionally substituted with oneor more lower alkoxy, (43) 3,4-dihydrocarbostyril optionally substitutedwith one or more lower alkoxy, (44) quinolyl optionally substituted withone or more substituents selected from the group consisting of aminooptionally substituted with one or two lower alkyl, lower alkoxy, loweralkyl and oxo, (45) chromanyl optionally substituted with one or morelower alkyl, (46) 5,6,7,8-tetrahydroisoquinolyl optionally substitutedwith one or more oxo, (47) 3,4-dihydro-1 H-isoquinolyl optionallysubstituted with one or more oxo, (48) naphthyridinyl, (49)1,4-benzodioxanyl, (50) cinnolinyl, (51) quinoxalinyl, or (52)2,3-dihydrobenz-1,4-oxazinyl optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl and oxo.3. The benzodiazepine compound of Formula (1) or a pharmaceuticallyacceptable salt thereof according to claim 2, wherein R⁶ and R⁷ are eachone of the following (4a), (6a), (7a), (15a), (30a), (31a), (32a),(33a), (40a) and (44a): (4a) phenyl optionally substituted with one ormore substituents selected from the group consisting of the following(4a-1), (4a-4) and (4a-6): (4a-1) cyano, (4a-4) lower alkyl optionallysubstituted with one or more halogen, and (4a-6) pyridyl, (6a) furyl,(7a) thienyl, (15a) pyridyl optionally substituted with one or morelower alkyl, (30a) furo[2,3-c]pyridyl optionally substituted with one ormore oxo, (31a) furo[3,2-c]pyridyl optionally substituted with one ormore substituents selected from the group consisting of oxo and loweralkyl, (32a) thieno[2,3-c]pyridyl optionally substituted with one ormore oxo, (33a) thieno[3,2-c]pyridyl optionally substituted with one ormore oxo, (40a) isoquinolyl optionally substituted with one or more oxo,and (44a) quinolyl optionally substituted with one or more oxo.
 4. Thebenzodiazepine compound of Formula (1) or a pharmaceutically acceptablesalt thereof according to claim 2, which is selected from the groupconsisting of the following compounds:1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride,3,3,5-trimethyl-1-propyl-7-{3-[(2-pyridin-3-ylethy)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride,1,5-diethyl-3,3-dimethyl-7-{3-[(2-pyridin-3-ylethy)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride,1,3,3,5-tetramethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride,1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride,1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride,N-methyl-N-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)benzamidedihydrochloride,1,3,3,5-tetramethyl-7-{3-[(2-methylbenzyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride,1,3,3,5-tetramethyl-7-{3-[(2-pyridin-3-ylethyl)-(quinolin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride,1-ethyl-3,3,5-trimethyl-7-{3-[(3-methylpyridin-4-ylmethyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionetrihydrochloride,1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-oxo-2H-quinolin-1-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride,1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride,4-({[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}methyl)benzonitrile,1-ethyl-3,3,5-trimethyl-7-(3-{[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]thiophen-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,1-ethyl-7-(3-{furan-2-ylmethyl-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,7-{3-[benzyl-(2-pyridin-3-ylethyl)amino]propoxy}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,3-{[[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-(2-pyridin-3-ylethyl)amino]methyl}benzonitrile,1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylbenzyl)-(2-pyridin-3-ylethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,4-({[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino(methyl)benzonitrile,1-ethyl-3,3,5-trimethyl-7-{3-[[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-(4-trifluoromethylbenzyl)amino]propoxy}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione,1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylbenzyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,1-ethyl-3,3,5-trimethyl-7-(3-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]thiophen-2-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,1-ethyl-3,3,5-trimethyl-7-(3-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dionedihydrochioride,1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyridin-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,1-ethyl-3,3,5-trimethyl-7-(3-{[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]pyridin-3-ylmethylamino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(4-methylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,1-ethyl-3,3,5-trimethyl-7-(3-{(4-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,1-ethyl-3,3,5-trimethyl-7-(3-{(2-methylpyridin-3-ylmethyl)-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,1-ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(2-propylpyridin-3-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride,N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamidehydrochloride,7-(3-{(2,6-dimethylpyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dionedihydrochloride,N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzamidehydrochloride, andN-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide.5. A pharmaceutical composition comprising a benzodiazepine compound ofFormula (1) or a pharmaceutically acceptable salt thereof according toclaim 1, and a pharmacologically acceptable carrier.
 6. Thepharmaceutical composition according to claim 5 for preventing and/ortreating arrhythmia in the form of tablets, pills, powders, solutions,suspensions, emulsions, granules, capsules, suppositories or injections.7. A method of treating arrhythmia, comprising administering to apatient in need thereof a benzodiazepine compound of Formula (1) or apharmaceutically acceptable salt thereof according to claim 1.